Piperazine-Substituted Benzothiophenes For Treatment of Mental Disorders

ABSTRACT

The present invention provides a heterocyclic compound represented by the general formula (1): The compound of the present invention has a wide treatment spectrum for mental disorders including central nervous system disorders, no side effects and high safety.

TECHNICAL FIELD

The present invention relates to a novel heterocyclic compound.

BACKGROUND ART

Since causal factor of schizophrenia as well as of bipolar disorder,mood disorders and emotional disorders is heterogeneous, it is desirablethat a drug has multiple pharmacological effects so as to develop widetreatment spectrum.

WO2004/026864A1 discloses that a carbostyril derivative represented bythe general formula:

(wherein A′ represents —(CH₂)_(m)CH₂—, —(CH₂)_(m)O—, etc.; m representsan integer of 1 to 4; and R^(A) represents a hydrogen atom, a C₁₋₄ alkylgroup which may be substituted with 1 to 3 fluorine atoms, etc.) has D₂receptor antagonist activity and serotonin 2A (5-HT_(2A)) receptorantagonist activity and it is effective for treatment of schizophreniaand other central nervous system disorders).

However, there is no description in WO2004/026864A1 that carbostyrilderivatives described in the document have D₂ receptor partial agonistactivity, 5-HT_(2A) receptor antagonist activity, a receptor antagonistactivity and serotonin uptake inhibitory activity together and have awide treatment spectrum.

WO 2005/019215 A1 discloses the compounds represented by the followingformula:

(wherein A is —(CH₂)_(m)CH₂—, —(CH₂)_(m)O— or the like; m is an integerof 2 to 5; D is N, C or the like; Z and Q are independently N, C or CH,provided that at least one of Z and Q is N; X and Y are independently C,N or the like, and the bond between X and Y is a single or double bond;R¹ is hydrogen, (C₁-C₃)alkyl group or the like; R⁴, R⁵, R⁶ and R⁷ eachrepresents hydrogen, alkyl group or the like; and G represents a groupof monocyclic or bicyclic compound), which bind to dopamine D₂receptors. WO 2005/019215 A1 teaches that some compounds disclosedtherein have an activity as partial agonists of D₂ receptors or anactivity as antagonists of D₂ receptors, and may be effective for thetreatment of schizophrenia and other central nervous system.

However, WO 2005/019215 A1 does not specifically disclose the compoundsof the present invention.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide an antipsychotic drugwhich has a wider treatment spectrum, less side effects and excellenttolerability and safety as compared with well-known typical and atypicalantipsychotic drugs.

The present inventors have conducted intensive studies on theabove-described problem and consequently succeeded in synthesizing anovel compound which has dopamine D₂ receptor partial agonist activity(D₂ receptor partial agonist activity), serotonin 5-HT_(2A) receptorantagonist activity (5-HT_(2A) receptor antagonist activity) andadrenalin α₁ receptor antagonist activity (α₁ receptor antagonistactivity) and further has serotonin uptake inhibitory effect (orserotonin reuptake inhibitory effect) together in addition to theseeffects. The present invention has been completed based on this finding.

The present invention provides a heterocyclic compound represented bythe general formula (1):

[wherein ring Q represented by

represents

(wherein

represents —NH—CH₂—, —N═CH—, —CH₂—NH— or —CH═N—; and

-   -   the carbon-carbon bond        -               between the 3-position and 4-position of the heterocyclic            skeleton containing Z and Y represents a single bond or a            double bond);

the ring Q may have at least one substituent selected from the groupconsisting of a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a hydroxy group, a lower alkoxy group, a halogenatedlower alkyl group, an aryl group, an aryl lower alkyl group, an aryllower alkoxy group, an arylcarbonyl group, a lower alkenyloxy group, alower alkanoyl group, a lower alkanoyloxy group, a cycloalkyl group, acycloalkyl lower alkyl group, a halogen atom, a carbamoyl group whichmay have a lower alkyl group, a carboxy group, a lower alkoxycarbonylgroup, an amino group which may have a lower alkanoyl group, a nitrogroup, a hydroxy lower alkyl group, an amino lower alkyl group which mayhave a lower alkyl group, a thienyl group, a saturated 3- to 8-memberedheteromonocyclic group containing 1 to 2 nitrogen atoms-substitutedlower alkyl group and an oxo group;

R₂ represents a hydrogen atom or a lower alkyl group; and

A represents —O-A_(L)- (wherein A₁ represents an alkylene group whichmay be substituted with a hydroxy group (wherein the alkylene group maycontain one oxygen atom) or a lower alkenylene group) or a loweralkylene group;

provided that when A represents a lower alkylene group, the ring Qrepresents a bicyclic group selected from the group consisting of:

(wherein the carbon-carbon bond

-   -           represents a single bond or a double bond)] or a salt thereof.

The present invention provides a heterocyclic compound represented bythe general formula (1),

wherein the ring Q represents a bicyclic group selected from the groupconsisting of:

(wherein the carbon-carbon bond

-   -           between the 3-position and 4-position of the bicyclic        heterocyclic skeleton represents a single bond or a double        bond);

the ring Q may have 1 to 3 substituents selected from the groupconsisting of a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a hydroxy group, a lower alkoxy group, a halogenatedlower alkyl group, a phenyl group, a phenyl lower alkyl group, anaphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyllower alkoxy group, a benzoyl group, a lower alkenyloxy group, a loweralkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, acyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl groupwhich may have a lower alkyl group, a carboxy group, a loweralkoxycarbonyl group, an amino group which may have lower alkanoylgroup, a nitro group, a hydroxy lower alkyl group, an amino lower alkylgroup which may have a lower alkyl group, a thienyl group and asaturated 5- to 6-membered heteromonocyclic group containing 1 to 2nitrogen atoms-substituted lower alkyl group; and

A represents —O-A₁- (wherein A₁ represents a C1-C6 alkylene group whichmay be substituted with a hydroxy group (wherein the alkylene group maycontain one oxygen atom)), or a salt thereof.

The present invention provides a heterocyclic compound represented bythe general formula (1),

wherein the ring Q represents a bicyclic group selected from the groupconsisting of:

the ring Q may have 1 to 3 substituents selected from the groupconsisting of a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a hydroxy group, a lower alkoxy group, a halogenatedlower alkyl group, a phenyl group, a phenyl lower alkyl group, anaphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyllower alkoxy group, a benzoyl group, a lower alkenyloxy group, a loweralkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, acyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl groupwhich may have a lower alkyl group, a carboxy group, a loweralkoxycarbonyl group, an amino group which may have a lower alkanoylgroup, a nitro group, a hydroxy lower alkyl group, an amino lower alkylgroup which may have a lower alkyl group, a phenyl group, a thienylgroup and a pyrrolidinyl lower alkyl group; and

A represents —O-A₁- (wherein A₁ represents a C1-C6 alkylene group whichmay be substituted with a hydroxy group (wherein the alkylene group maycontain one oxygen atom)), or a salt thereof.

The present invention provides a heterocyclic compound represented bythe general formula (1),

wherein the ring Q represents a bicyclic group selected from the groupconsisting of:

(the ring Q may have 1 to 3 substituents selected from the groupconsisting of a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a hydroxy group, a lower alkoxy group, a halogenatedlower alkyl group, a phenyl group, a phenyl lower alkyl group, anaphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyllower alkoxy group, a benzoyl group, a lower alkenyloxy group, a loweralkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, acyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl groupwhich may have a lower alkyl group, a carboxy group, a loweralkoxycarbonyl group, an amino group which may have a lower alkanoylgroup, a nitro group, a hydroxy lower alkyl group, an amino lower alkylgroup which may have a lower alkyl group, a thienyl group and apyrrolidinyl lower alkyl group) or a salt thereof.

The present invention provides a heterocyclic compound represented bythe general formula (1),

wherein the ring Q represents a bicyclic group selected from the groupconsisting of:

(wherein the carbon-carbon bond

-   -           between the 3-position and 4-position of the above-mentioned        bicyclic heterocyclic skeleton represents a single bond or a        double bond);

the ring Q may have 1 to 3 substituents thereon selected from the groupconsisting of a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a hydroxy group, a lower alkoxy group, a halogenatedlower alkyl group, a phenyl group, a phenyl lower alkyl group, anaphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyllower alkoxy group, a benzoyl group, a lower alkenyloxy group, a loweralkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, acyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl groupwhich may have a lower alkyl group, a carboxy group, a loweralkoxycarbonyl group, an amino group which may have a lower alkanoylgroup, a nitro group, a hydroxy lower alkyl group, an amino lower alkylgroup which may have a lower alkyl group, a thienyl group, apyrrolidinyl lower alkyl group and an oxo group; and

A represents a lower alkylene group, or a salt thereof.

The present invention provides a heterocyclic compound represented bythe general formula (1),

wherein the ring Q represents a bicyclic group selected from the groupconsisting of:

(wherein the carbon-carbon bond

-   -           between the 3-position and 4-position of the above-mentioned        bicyclic heterocyclic skeleton represents a single bond or a        double bond);

the ring Q may have 1 to 3 substituents selected from the groupconsisting of a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a hydroxy group, a lower alkoxy group, a halogenatedlower alkyl group, a phenyl group, a phenyl lower alkyl group, anaphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyllower alkoxy group, a benzoyl group, a lower alkenyloxy group, a loweralkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, acyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl groupwhich may have a lower alkyl group, a carboxy group, a loweralkoxycarbonyl group, an amino group which may have a lower alkanoylgroup, a nitro group, a hydroxy lower alkyl group, an amino lower alkylgroup which may have a lower alkyl group, a thienyl group and apyrrolidinyl lower alkyl group, or a salt thereof.

Among the heterocyclic compounds or salts thereof represented by theformula (1), preferable compounds include a compound or a salt thereofselected from:

-   (1)    7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one,-   (2)    7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-quinolin-2-one,-   (3)    7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one,-   (4)    7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one,-   (5)    7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1-methyl-3,4-dihydro-1H-quinolin-2-one    and-   (6)    6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one;    or a salt thereof.

In addition, among the heterocyclic compounds or salts thereofrepresented by the formula (1), preferable compounds include a compoundor a salt thereof selected from:

-   (1)    7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-one-   (2)    7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one,-   (3)    7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one,-   (4)    7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-2H-isoquinolin-1-one,-   (5) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)    propoxy]-2H-isoquinolin-1-one and-   (6)    7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-2H-isoquinolin-1-one;    or a salt thereof.

The present invention provides a pharmaceutical composition comprising aheterocyclic compound represented by the formula (1) or a salt thereofas an active ingredient mixed with a pharmaceutically acceptablecarrier. The pharmaceutical composition according to the presentinvention can be effectively used for the treatment or prevention ofcentral nervous system disorders.

The pharmaceutical composition according to the present invention can beused as a pharmaceutical composition for treating or preventing centralnervous system disorders selected from the group consisting ofschizophrenia; refractory, intractable or chronic schizophrenia;emotional disturbance; psychotic disorder; mood disorder; bipolar I typedisorder; bipolar II type disorder; depression; endogenous depression;major depression; melancholy and refractory depression; dysthymicdisorder; cyclothymic disorder; panic attack; panic disorder;agoraphobia; social phobia; obsessive-compulsive disorder;post-traumatic stress disorder; generalized anxiety disorder; acutestress disorder; hysteria; somatization disorder; conversion disorder;pain disorder; hypochondriasis; factitious disorder; dissociativedisorder; sexual dysfunction; sexual desire disorder; sexual arousaldisorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleepdisorder; adjustment disorder; alcohol abuse; alcohol intoxication; drugaddiction; stimulant intoxication; narcotism; anhedonia; iatrogenicanhedonia; anhedonia of a psychic or mental cause; anhedonia associatedwith depression; anhedonia associated with schizophrenia; delirium;cognitive impairment; cognitive impairment associated with Alzheimer'sdisease, Parkinson's disease and other neurodegenerative diseases;cognitive impairment caused by Alzheimer's disease, Parkinson's diseaseand associated neurodegenerative diseases; cognitive impairment ofschizophrenia; cognitive impairment caused by refractory, intractable orchronic schizophrenia; vomiting; motion sickness; obesity; migraine;pain (ache); mental retardation; autism disorder (autism); Tourette'sdisorder; tic disorder; attention-deficit/hyperactivity disorder;conduct disorder; and Down's syndrome.

The present invention provides a process for producing a pharmaceuticalcomposition comprising mixing a heterocyclic compound represented by theabove-described formula (1) or a salt thereof with a pharmaceuticallyacceptable carrier.

The present invention provides use of a heterocyclic compoundrepresented by the above-described formula (1) or a salt thereof as adrug.

Specifically provided is of a heterocyclic compound represented by theabove-described formula (1) or a salt thereof, as a dopamine D₂ receptorpartial agonist and/or a serotonin 5-HT_(2A) receptor antagonist and/oran adrenaline a receptor antagonist and/or a serotonin uptake inhibitor(or a serotonin reuptake inhibitor).

The present invention provides a method for treating or preventing acentral nervous system disorder comprising administering a compoundrepresented by the above-described formula (1) or a salt thereof tohuman or animal.

The present invention provides a process for producing a heterocycliccompound represented by the above-described formula (1):

or a salt thereof, characterized by comprising a reaction of a compoundrepresented by the formula:

(wherein the ring Q and A are the same as defined above, and X₁represents a halogen atom or a group which causes a substitutionreaction the same as in a halogen atom) or a salt thereof with acompound represented by the formula:

(wherein R₂ is the same as defined above) or a salt thereof.

Specifically, respective groups shown in the above general formula (1)are as follows.

As a lower alkyl group, a linear or branched alkyl group having 1 to 6carbon atoms can be mentioned. More specifically, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl,3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl groups areincluded.

As a lower alkoxy group, a linear or branched alkoxy group having 1 to 6carbon atoms can be mentioned. More specifically, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy,n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy,3-methylpentyloxy groups are included.

As a lower alkenyl group, a linear or branched alkenyl group having 1 to3 double bonds and 2 to 6 carbon atoms can be mentioned including theboth of trans and cis configurations. More specifically, vinyl,1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl,2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl,1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5-hexenyl,3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl,1,3,5-hexatrienyl, 1,3-hexadienyl, 1,4-hexadienyl groups are included.

As a lower alkynyl group, a linear or branched alkynyl group having 2 to6 carbon atoms can be mentioned. More specifically, ethynyl, 2-propynyl,2-butynyl, 3-butynyl, l-methyl-2-propynyl, 2-pentynyl, 2-hexynyl groupsare included.

As a halogen atom, fluorine atom, chlorine atom, bromine atom and iodineatom can be mentioned.

As a halogenated lower alkyl group, a lower alkyl group as illustratedabove substituted with 1 to 7 halogen atoms, preferably 1 to 3 halogenatoms can be mentioned. More specifically, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,bromomethyl, dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl,3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl,heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl,4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl,4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, 5-chloropentyl,6,6,6-trifluorohexyl, 6-chlorohexyl, perfluorohexyl are included.

As an aryl group, for example, phenyl, biphenyl, naphthyl groups can bementioned and as a substituent on the phenyl ring or naphthalene ring, alower alkyl group (preferably linear or branched alkyl group having 1 to6 carbon atoms) as illustrated above, lower alkoxy group (preferablylinear or branched alkoxy group having 1 to 6 carbon atoms) asillustrated above, and phenyl, biphenyl, or naphthyl groups which mayhave 1 to 3 groups selected from a nitro group and a halogen atom areincluded.

Specific examples of an aryl group include phenyl, 2- (or 3- or4-)methylphenyl, 2- (or 3- or 4-)nitrophenyl, 2- (or 3- or4-)methoxyphenyl, 2- (or 3- or 4-)chlorophenyl, biphenyl, α-naphthyl,β-naphthyl groups.

As an aryl lower alkyl group, a lower alkyl group (preferably linear orbranched alkyl group having 1 to 6 carbon atoms) as illustrated abovewhich has 1 to 3, preferably one aryl group as illustrated above can bementioned.

Specific examples of an aryl lower alkyl group include benzyl, 2- (or 3-or 4-)methylbenzyl, 2- (or 3- or 4-) nitrobenzyl, 2- (or 3- or4-)methoxybenzyl, 2- (or 3- or 4-) chlorobenzyl, 1- (or 2-)phenylethyl,1-methyl-1-phenylethyl, 1,1-dimethyl-2-phenylethyl,1,1-dimethyl-3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl groups.

As an aryl lower alkoxy group, a lower alkoxy group (preferably linearor branched alkoxy group having 1 to 6 carbon atoms) as illustratedabove which has 1 to 3, preferably one aryl group as illustrated abovecan be mentioned. Specific examples of an aryl lower alkoxy groupinclude benzyloxy, 2- (or 3- or 4-)methylbenzyloxy, 2- (or 3- or 4-)nitrobenzyloxy, 2-(or 3- or 4-)methoxy benzyloxy, 2- (or 3- or4-)chlorobenzyl, 1- (or 2-)phenylethoxy, 1-methyl-1-phenyl ethoxy,1,1-dimethyl-2-phenyl ethoxy, 1,1-dimethyl-3-phenyl propoxy,α-naphthylmethoxy, β-naphthylmethoxy groups.

As an aryl moiety of an arylcarbonyl group, an aryl group as illustratedabove can be mentioned. Specific examples of an arylcarbonyl groupinclude benzoyl, 2- (or 3- or 4-)methylbenzoyl, 2- (or 3- or4-)nitrobenzoyl, 2- (or 3- or 4-)methoxybenzoyl, 2- (or 3- or4-)chlorobenzoyl, α-naphthoyl, β-naphthoyl groups.

As a lower alkenyloxy group, a lower alkenyloxy group having a loweralkenyl group (preferably a linear or branched alkenyloxy group having 1to 3 double bonds and 2 to 6 carbon atoms) as illustrated above can bementioned. More specifically included are vinyloxy, 1-propenyloxy,1-methyl-1-propenyloxy, 2-methyl-1-propenyloxy, 2-propenyloxy,2-butenyloxy, 1-butenyloxy, 3-butenyloxy, 2-pentenyloxy, 1-pentenyloxy,3-pentenyloxy, 4-pentenyloxy, 1,3-butadienyloxy, 1,3-pentadienyloxy,2-penten-4-yloxy, 2-hexenyloxy, 1-hexenyloxy, 5-hexenyloxy,3-hexenyloxy, 4-hexenyloxy, 3,3-dimethyl-1-propenyloxy,2-ethyl-1-propenyloxy, 1,3,5-hexatrienyloxy, 1,3-hexadienyloxy,1,4-hexadienyloxy groups.

As a lower alkanoyl group, a linear or branched alkanoyl group having 1to 6 carbon atoms can be mentioned. More specifically, formyl, acetyl,propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoylgroups are included.

As a lower alkanoyloxy group, a linear or branched alkanoyloxy grouphaving 1 to 6 carbon atoms can be mentioned. More specifically,formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,pentanoyloxy, tert-butylcarbonyloxy, hexanoyloxy groups are included.

As a cycloalkyl group, a cyclo C3-C8 alkyl group having 3 to 8 carbonatoms can be mentioned. Examples thereof include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl groups.

As a cycloalkyl lower alkyl group, a lower alkyl group as illustratedabove which has 1 to 3, preferably one cycloalkyl group (preferably,cyclo C3-C8 alkyl group having 3 to 8 carbon atoms) as illustrated abovecan be mentioned. More specifically included are cyclopropylmethyl,cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl,cyclopentylmethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl,5-cycloheptylpentyl, 6-cyclooctylhexyl, 1,1-dimethyl-2-cyclohexylethyl,2-methyl-3-cyclopropylpropyl groups.

As a carbamoyl group which may have a lower alkyl group, a carbamoylgroup which may have 1 to 2 lower alkyl group (preferably, alkyl grouphaving 1 to 6 carbon atoms) as illustrated above can be mentioned. Morespecifically included are carbamoyl, N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl groups.

As a lower alkoxycarbonyl group, those having a lower alkoxy moiety asillustrated above, preferably a linear or branched alkoxycarbonyl grouphaving 1 to 6 carbon atoms can be mentioned. More specifically includedare methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl,neopentyloxy, n-hexyloxy carbonyl, isohexyloxycarbonyl,3-methylpentyloxycarbonyl groups.

As an amino group which may have a lower alkanoyl group, those havingone lower alkanoyl group as illustrated above (preferably a linear orbranched alkanoyl group having 1 to 6 carbon atoms) can be mentioned.More specifically, examples include amino, N-formylamino, N-acetylaminogroups.

As a hydroxy lower alkyl group, a lower alkyl group (preferably, alinear or branched alkyl group having 1 to 6 carbon atoms) asillustrated above having 1 to 5, preferably 1 to 3 hydroxy groups can bementioned. More specifically included are hydroxymethyl, 2-hydroxyethyl,1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl,3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl,6-hydroxyhexyl, 3,3-dimethyl-3-hydroxypropyl, 2-methyl-3-hydroxypropyl,2,3,4-trihydroxybutyl, perhydroxyhexyl groups.

As an amino lower alkyl group which may have a lower alkyl group, alower alkyl group (preferably, a linear or branched alkyl group having 1to 6 carbon atoms) as illustrated above having 1 to 5, preferably oneamino group which may have 1 to 2 lower alkyl group (preferably, alinear or branched alkyl group having 1 to 6 carbon atoms) asillustrated above can be mentioned. More specifically, examples of suchan amino lower alkyl group which may have a lower alkyl group includeaminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl,5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-methyl-3-aminopropyl,N,N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl,N-methylaminomethyl, 2-(N-methylamino)ethyl,1-methyl-2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethyl,2-(N,N-diethylamino)ethyl, 2-(N,N-diisopropylamino)ethyl,3-(N,N-dimethylamino)propyl, 3-(N,N-diethylamino)propyl groups.

As a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2nitrogen atoms group, for example, azetidinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl morpholinyl,thiomorpholinyl groups (preferably a saturated 5- to 6-memberedheteromonocyclic group containing 1 to 2 nitrogen atoms group such aspyrrolidinyl, imidazolidinyl, piperidinyl, piperidino, pyrazolidinyl andpiperazinyl) can be mentioned.

As a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2nitrogen atoms-substituted lower alkyl group, a lower alkyl (preferably,a linear or branched alkyl group having 1 to 6 carbon atoms) asillustrated above having 1 to 2 (preferably one) a saturated 3- to8-membered (preferably 5- to 6-membered) heteromonocyclic groupcontaining 1 to 2 nitrogen atoms as illustrated above can be mentioned.More specifically, [(1-, 2- or 3-)azetidinyl]methyl, [(1-, 2- or3-)pyrrolidinyl]methyl, [(1-, 2- or 4-)-imidazolidinyl]methyl, [(1-, 3-or 4-)-pyrazolidinyl]methyl, [(1-, 2-, 3- or 4-)-piperidyl]methyl, [(2-,3- or 4-)morpholinyl]methyl, 2-[(1-, 2- or 3-)pyrrolidinyl]ethyl,1-[(1-, 2- or 3-)-pyrrolidinyl]ethyl, 3-[(1-, 2- or 3-)piperidyl]propyl,4-[(1-, 2- or 3-)pyrrolidinyl]butyl, 5-[(1-, 2- or 3-)-piperidyl]pentylare included.

Examples of an alkylene group which may be substituted with a hydroxygroup (wherein the alkylene group may contain one oxygen atom) include alinear or branched alkylene group (wherein the alkylene group maycontain one oxygen atom) having 1 to 12 (preferably 1 to 6) carbon atomssuch as methylene, ethylene, trimethylene, 2-methyltrimethylene,2-hydroxytrimethylene, 3-hydroxytetramethylene, 3-methyltetramethylene,2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene,ethylmethylene, tetramethylene, pentamethylene, hexamethylene,2-ethoxyethylene (—CH₂CH₂OCH₂CH₂—), methoxymethylene (—CH₂OCH₂—),1-ethoxyethylene (—CH₂CH₂OCH(CH₃)—), 2-methoxyethylene (—CH₂OCH₂CH₂—),2-propoxyethylene (—CH₂CH₂CH₂OCH₂CH₂—), 3-isopropoxytrimethylene(—CH(CH₃) CH₂OCH₂CH₂—), 4-butoxytetramethylene(—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂—), 5-pentyloxypentamethylene(—CH₂CH₂CH₂CH₂CH₂OCH₂C₂CH₂CH₂C₂—), 6-hexyloxyhexamethylene(—CH₂CH₂CH₂CH₂CH₂CH₂OCH₂CH₂CH₂CH₂CH₂CH₂—), 1,1-dimethyl-2-methoxyethylene (—CH₂OCH₂C(CH₃)₂—),2-methyl-3-ethoxytrimethylene (—CH₂CH₂OCH₂CH(CH₃) CH₂—),3-methoxytrimethylene (—CH₂OCH₂CH₂CH₂CH₂—) groups.

Examples of a lower alkenylene group include a linear or branchedalkenylene group having 1 to 3 double bonds and 2 to 6 carbon atoms suchas vinylene, 1-propenylene, 1-methyl-1-propenylene,2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene,3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene,4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-pentene-4-ylene,2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4-hexenylene,3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene,1,3-hexadienylene, 1,4-hexadienylene groups.

Examples of a lower alkylene group include a linear or branchedalkenylene group having 1 to 6 carbon atoms such as methylene, ethylene,trimethylene, 2-methyltrimethylene, 3-methyltetramethylene,2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene,ethylmethylene, tetramethylene, pentamethylene and hexamethylene groups.

The heterocyclic compound represented by the above-described generalformula (1) can be produced in various kinds of methods, but, forexample, it can be produced by a method shown in the following reactionformula.

(wherein ring Q, A and R₂ are the same as defined above, and X₁represents a halogen atom or a group which causes a substitutionreaction the same as in a halogen atom).

Here, examples of a group which causes a substitution reaction the sameas in a halogen atom include a lower alkanesulfonyloxy group, anarylsulfonyloxy group and an aralkylsulfonyloxy group.

A halogen atom shown as X₁ in the general formula (2) is the same asdefined above.

As a lower alkanesulfonyloxy group shown as X₁, examples include alinear or branched alkanesulfonyloxy group having 1 to 6 carbon atomssuch as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy,isopropanesulfonyloxy, n-butanesulfonyloxy, tert-butanesulfonyloxy,n-pentanesulfonyloxy and n-hexanesulfonyloxy groups.

As an arylsulfonyloxy group shown as X₁, examples includephenylsulfonyloxy and naphthylsulfonyloxy groups which may have 1 to 3substituents selected from the group consisting of a linear or branchedalkyl group having 1 to 6 carbon atoms, a linear or branched alkoxygroup having 1 to 6 carbon atoms, a nitro group and a halogen atom onthe phenyl ring, for example. Specific examples of a phenylsulfonyloxygroup which may have a substituent include phenylsulfonyloxy,4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,4-nitrophenylsulphonyloxy, 4-methoxyphenylsulfonyloxy,2-nitrophenylsulphonyloxy, 3-chlorophenylsulphonyloxy groups. Specificexamples of a naphthylsulfonyloxy group include α-naphthyl sulfonyloxy,β-naphthyl sulfonyloxy groups.

As an aralkylsulfonyloxy group shown as X₁, examples include a linear orbranched alkanesulfonyloxy group having 1 to 6 carbon atoms andsubstituted with a phenyl group, a linear or branched alkanesulfonyloxygroup having 1 to 6 carbon atoms and substituted with a naphthyl group,which groups which may have 1 to 3 substituents selected from the groupconsisting of a linear or branched alkyl group having 1 to 6 carbonatoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, anitro group and a halogen atom on the phenyl ring, for example. Specificexamples of a phenylsulfonyloxy group substituted with a naphthyl groupas mentioned above include benzylsulfonyloxy, 2-phenylethylsulfonyloxy,4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy,2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy,4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy groups. Specificexamples of an alkanesulfonyloxy group substituted with a naphthyl groupas mentioned above include α-naphthylmethyl sulfonyloxy,β-naphthylmethyl sulfonyloxy groups.

The reaction of a compound represented by the general formula (2) and acompound represented by the general formula (3) is performed withoutsolvent or in an inert solvent in the absence or presence of a basiccompound.

Examples of an inert solvent include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether,ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene,toluene, xylene; lower alcohols such as methanol, ethanol, isopropanol;ketones such as acetone, methyl ethyl ketone; polar solvents such asN,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),hexamethylphosphoric triamide, acetonitrile.

As a basic compound, known compounds can be widely used and examplesinclude alkali metal hydroxides such as sodium hydroxide, potassiumhydroxide, cesium hydroxide, lithium hydroxide; alkali metal carbonatessuch as sodium carbonate, potassium carbonate, cesium carbonate, lithiumcarbonate; alkaline metal hydrogen carbonates such as lithium hydrogencarbonate, sodium hydrogen carbonate, potassium bicarbonate; alkalinemetals such as sodium, potassium; inorganic bases such as sodium amide,sodium hydride, potassium hydride and alkaline metal alcoholates such assodium methoxide, sodium ethoxide, potassium methoxide, potassiumethoxide; organic bases such as triethylamine, tripropylamine, pyridine,quinoline, piperidine, imidazole, N-ethyldiisopropylamine,dimethylaminopyridine, trimethylamine, dimethylaniline,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO).

As for these basic compounds, one kind of compound alone or two or morein combination can be used.

The amount to be used of a basic compound is usually 0.5 to 10 times,preferably 0.5 to 6 times molar amount of a compound of the generalformula (2).

The above-described reaction can be performed with addition of analkaline metal iodide such as potassium iodide, sodium iodide as areaction accelerator, if necessary.

As for the ratio to be used of a compound of the general formula (2) anda compound of the general formula (3) in the above-mentioned reactionFormula 1, the latter may be usually at least 0.5 times, preferably, 0.5to 5 times molar amount of the former.

The above-described reaction is performed usually from room temperatureto 200° C., preferably from room temperature to 150° C. and generallycompleted in about 1 to 30 hours.

(wherein ring Q, R₂ and A₁ are the same as defined above. X₂ representsa hydroxy group, a halogen atom or a group which causes a substitutionreaction similar to a halogen atom).

The reaction of a compound represented by the general formula (4) and acompound represented by the general formula (5a) is performed undersimilar reaction condition as in the reaction of a compound representedby the general formula (2) and a compound represented by the generalformula (3) in the above-mentioned Reaction Formula 1.

In the case of a compound (5a) in which X₂ represents a hydroxy group,the reaction of a compound (4) and a compound (5a) can be performed inan appropriate solvent in the presence of a condensing agent.

As for the solvent usable here, specific examples include halogenatedhydrocarbons such as chloroform, dichloromethane, dichloroethane, carbontetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene;ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,dimethoxyethane; esters such as methyl acetate, ethyl acetate, isopropylacetate; polar solvent such as acetonitrile, pyridine, acetone, DMF,DMSO, hexamethylphosphoric triamide or a mixed solvent of these.

As a condensing agent, azocarboxylates such as diethyl azodicarboxylateand a mixture of phosphorus compounds such as triphenylphosphine can bementioned.

The amount of a condensing agent to be used is usually at leastequimolar, preferably equimolar to 2 times the amount of compound (4).

The amount of compound (5a) to be used is usually at least equimolar,preferably equimolar to 2 times the amount of compound (4).

This reaction precedes usually 0 to 200° C., preferably 0 to 150° C. andgenerally completed in about 1 to 10 hours.

[wherein R₂ is the same as above, X₃ represents a halogen atom or agroup which causes a substitution reaction similar to a halogen atom, A₂represents a lower alkylene group, and

the ring Q1 represents a bicyclic group selected from the groupconsisting of:

(wherein the carbon-carbon bond

-   -           represents a single bond or a double bond);

the ring Q1 may have at least one substituent selected from the groupconsisting of a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a hydroxy group, a lower alkoxy group, an aryl group, anaryl lower alkyl group, an aryl lower alkoxy group, a lower alkenyloxygroup, a lower alkanoyl group, a lower alkanoyloxy group, a cycloalkylgroup, a cycloalkyl (lower) alkyl group, a halogen atom, a carbamoylgroup which may have a lower alkyl group, a carboxy group, a loweralkoxycarbonyl group, an amino group which may have a lower alkanoylgroup, a nitro group, a hydroxy lower alkyl group, an amino lower alkylgroup which may have a lower alkyl group, a thienyl group, a saturated3- to 8-membered heteromonocyclic group containing 1 to 2 nitrogenatoms-substituted lower alkyl group and an oxo group].

The reaction of a compound represented by the general formula (6) and acompound represented by the general formula (5b) is performed undersimilar reaction condition as in the reaction of a compound representedby the general formula (2) and a compound represented by the generalformula (3) in the above-mentioned Reaction Formula 1.

The compound represented by the general formula (2), which is used as astarting material, can be produced, for example, according to thefollowing reaction Formula 4 and the compound represented by the generalformula (5) can be produced, for example, according to the ReactionFormula 5 below respectively.

(wherein ring Q, A₁, X₁ and X₃ are the same as above) The reaction of acompound represented by the general formula (4) and a compoundrepresented by the general formula (8) is performed under similarreaction condition as in the reaction of a compound represented by thegeneral formula (4) and a compound represented by the general formula(5a) in the above-mentioned Reaction Formula 2.

(wherein R₂, A and X₂ are the same as above, and X₄ represents a halogenatom or a group which causes a substitution reaction the same as in ahalogen atom).

The reaction of a compound represented by the general formula (3) and acompound represented by the general formula (9) is performed undersimilar reaction condition as in the reaction of a compound representedby the general formula (2) and a compound represented by the generalformula (3) in the above-mentioned Reaction Formula 1. Both the compoundof the general formula (3) and the compound of the general formula (9)are well-known compounds readily available.

In compound (1), a compound having a hydroxy group at ring Q can beproduced by treating a compound having a methoxy group at ring Q incompound (1) in the presence of an acid in an appropriate solvent orwithout solvent.

As for inert solvent usable here, examples include water; aromatichydrocarbons such as benzene, toluene, xylene; ethers such as diethylether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenatedhydrocarbons such as dichloromethane, dichloroethane, chloroform, carbontetrachloride; lower alcohols such as methanol, ethanol, isopropanol,butanol, tert-butanol, ethylene glycol; fatty acids such as acetic acid;esters such as ethyl acetate, methyl acetate; ketones such as acetone,methyl ethyl ketone; acetonitrile, pyridine, DMF, DMSO,hexamethylphosphoric triamide or a mixed solvent of these.

As for the acid, examples include mineral acids such as hydrobromicacid, hydrochloric acid, concentrated sulfuric acid; fatty acids such asformic acid, acetic acid, organic acids such as p-toluenesulfonic acid;Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tinchloride, boron trifluoride, boron tribromide; iodides such as sodiumiodide, potassium iodides; a mixture of a Lewis acid and an iodide asmentioned above.

It is suitable that such an acid is usually used at 0.1 to 15 times,preferably 0.5 to 10 times molar amount of compound (1). When thereaction is effected without solvent, the acid is usually used in alarge excess amount.

This reaction is performed usually 0 to 150° C., preferably at around 0to 100° C., and generally completed for about 0.5 to 75 hours.

The starting compounds used in each of the above reaction formula may besuitable salt, the object compound obtained by each of the reaction mayform a suitable salt. Such suitable salts include the preferable saltsof compound (1) exemplified below.

The preferable salts of compound (1) are pharmacologically acceptablesalts and examples include metal salts such as alkali metal salts (forexample, sodium salt potassium salt, etc.), alkaline earth metal salts(for example, calcium salt, magnesium salt, etc.), salts of inorganicbases such as ammonium salt, alkaline metal carbonates (for example,lithium carbonate, potassium carbonate, sodium carbonate, cesiumcarbonate, etc.), alkaline metal hydrogen carbonates (for example,lithium hydrogen carbonate, sodium hydrogen carbonate, potassiumbicarbonate, etc.), alkali metal hydroxides (for example, lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide,etc.); for example, salts of organic bases such as tri(lower)alkylamine(for example, trimethylamine, triethylamine, N-ethyldiisopropylamine),pyridine, quinoline, piperidine, imidazole, picoline,dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (forexample, N-methylmorpholine), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO); salts of inorganic acids such as hydrochloride, hydrobromide,hydroiodide, sulfate, nitrate, phosphate; salts of organic acids such asformate, acetate, propionate, oxalate, malonate, succinate, fumarate,maleate, lactate, malate, citrate, tartrate, carbonate, picrate,methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate.

In addition, compounds in the form in which solvate (for example,hydrate, ethanolate, etc.) was added to the starting compounds andobject compound shown in each of the reaction formulae are included ineach of the general formulas. As a preferable solvate, hydrate can bementioned.

Each of the object compounds obtained by each of the general formulascan be isolated and purified from the reaction mixture by, for example,subjecting the reaction mixture to isolation operation such asfiltration, concentration and extraction after cooling to separate acrude reaction product followed by conventional purification operationsuch as column chromatography or recrystallization.

The compound represented by the general formula (1) of the presentinvention naturally encompasses isomers such as geometrical isomer,stereoisomer and enantiomer.

The compound of the general formula (1) and a salt thereof can be usedin a common form of pharmaceutical preparation. The pharmaceuticalpreparation is prepared by using usually used diluent or excipient suchas filler, extending agent, binder, humectant, disintegrating agent,surfactant and lubricant. As for this pharmaceutical preparation,various forms can be selected depending on the purpose of treatment, andtypical examples include a tablet, pill, powder, solution, suspension,emulsion, granule, capsule, suppository, and injection (solution,suspension).

For shaping in tablet form, various materials conventionally well knownas carrier in the art can be widely used. As examples, excipient such aslactose, saccharose, sodium chloride, glucose, urea, starch, calciumcarbonate, kaolin, crystalline cellulose, silicate; binder such aswater, ethanol, propanol, simple syrup, glucose solution, starch liquid,gelatine solution, carboxymethylcellulose, shellac, methylcellulose,potassium phosphate, polyvinylpyrrolidone; disintegrating agent such asdried starch, sodium alginate, agar powder, laminaran powder, sodiumhydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fattyacid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch,lactose; disintegration preventing agent such as saccharose, stearin,cacao butter, hydrogenated oil; sorbefacient such as quaternary ammoniumbase, sodium lauryl sulfate; moisturizing agent such as glycerine,starch; absorbing agent such as starch, lactose, kaolin, bentonite,colloidal silica; lubricant such as purified talc, stearate, boratepowder, polyethylene glycol can be used, for example. Furthermore, thetablet may be a tablet provided with conventional coating as required,for example, sugar-coated tablet, gelatine encapsulated tablet, entericcoating tablet, film coated tablet or double tablet, multilayer tablet.

For shaping in pill form, various materials conventionally well known ascarrier in the art can be widely used. As examples, excipient such asglucose, lactose, starch, cacao butter, hydrogenated vegetable oil,kaolin, talc; binder such as powdered gum arabic, powdered tragacanth,gelatine, ethanol; disintegrating agent such as laminaran, agar can beused, for example.

For shaping in suppository form, various materials conventionally wellknown as carrier can be widely used. Examples thereof includepolyethylene glycol, cacao butter, higher alcohol, esters of higheralcohol, gelatine, semisynthesized glyceride, for example.

A capsule is usually prepared according to a conventional method bymixing active ingredient compounds with various carrier exemplifiedabove and filling them into a hard gelatin capsule, a soft capsule orthe like.

When prepared as injection liquid, it is preferable that solution,emulsion and suspension are sterilized and isotonic to the blood and forforming in these modes, any of those conventionally used in the art asdiluent can be used, and, for example, water, ethyl alcohol, macrogol,propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, etc. canbe used.

The pharmaceutical preparation may contain common salt, glucose orglycerine in an amount sufficient to prepare an isotonic solution inthis case, and conventional solubilizer, buffer, soothing agent may bealso added. Pigment, preservative, aromatic, flavor, sweetening andother pharmaceuticals may be further contained as required.

The amount of a compound of the general formula (1) or a salt thereof tobe contained in the pharmaceutical preparation of the present inventionis not particularly limited but usually about 1 to 70% by weight in thepreparation composition is suitable and preferably about 1 to 30% byweight.

There is not limitation in particular in the way of administration ofthe pharmaceutical preparation of the present invention and may beadministered by a method in accordance with specific form of thepreparation, age, sex and the other conditions of a patient, severity ofdisease, etc. For example, in the case of tablet, pill, solution,suspension, emulsion, granule and capsule, it is orally administered. Inthe case of injection, it is intravenously administered alone or in amixture with conventional replacement fluid such as glucose and aminoacids, and if necessary, and the preparation alone may be alsoadministered intramuscularly, intracutaneously, subcutaneously orinterperitoneally. It is administered in rectum in the case ofsuppository.

Applied dose of the pharmaceutical preparation of the present inventionis appropriately selected in accordance with dosage regimen, age, sexand the other conditions of a patient, severity of disease, etc., but itis suitable that the amount of the active ingredient compound is usuallyabout 0.1 to 10 mg per 1 kg of body weight per day. In addition, it isdesirable that the active ingredient compound is contained in thepreparation of a dosage unit form in the range of about 1 to 200 mg.

The compound of the present invention has D₂ receptor partial agonisteffect, 5-HT_(2A) receptor antagonist effect and serotonin uptakeinhibitory effect (or serotonin uptake inhibitory effect).

The D₂ receptor partial agonist effect suppresses dopaminergic (DA)neurotransmission when it is enhanced, and accelerates the DAneurotransmission when it is lowered and thus has a function tostabilize the DA neurotransmission to a normal state (dopamine systemstabilizer). According to this function, excellent clinically improvingeffect on the conditions based on the DA abnormal neurotransmission(enhancement and lowering), for example, improving effect on positiveand negative symptoms, improving effect on cognitive impairment,improving effect on depressive symptom, etc. are developed withoutdeveloping side effects (See Michio Toru: Seishin-Igaku (Psychiatry),Vol. 46, pp. 855-864 (2004), Tetsuro Kikuchi and Tsuyoshi Hirose:Nou-no-Kagaku (Brain Science), Vol. 25, pp. 579-583 (2003) and Harrison,T. S. and Perry, C. M.: Drugs 64: 1715-1736, 2004).

5-HT_(2A) receptor antagonist effect reduces extrapyramidal sideeffects, develops superior clinical effects, and is effective forimprovement of negative symptoms, improvement of cognitive impairment,improvement of depression condition, improvement of insomnia, forexample (See Jun Ishigooka and Ken Inada: Rinsho-Seishin-Yakuri(Japanese Journal of Clinical Psychopharmacology), Vol. 4, pp. 1653-1664(2001), Mitsukuni Murasaki: Rinsho-Seishin-Yakuri (Japanese Journal ofClinical Psychopharmacology), Vol. 1, pp. 5-22 (1998), Puller, I. A. etal., Eur. J. Pharmacol., 407:39-46, 2000, and Meltzer, H. Y. et al,Prog. Neuro-Psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).

Serotonin uptake inhibitory effect (or serotonin reuptake inhibitoryeffect) is effective for improving depressive symptoms, for example (SeeMitsukuni Murasaki: Rinsho-Seishin-Yakuri (Japanese Journal of ClinicalPsychopharmacology), Vol. 1, pp. 5-22 (1998)).

The compounds of the present invention are excellent in all of thesethree effects, or remarkably excellent in one or two of these effects.

In addition, some of the compounds of the present invention have α₁receptor antagonist effect in addition to the above-described effects.The α₁ receptor antagonist effect is effective for improving positivesymptoms of schizophrenia (See Svensson, T. H.: Prog.Neuro-Psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003).

Therefore, the compounds of the present invention have a wide treatmentspectrum for and excellent clinical effect on schizophrenia and othercentral nervous system disorders.

Accordingly, the compounds of the present invention are extremelyeffective for the treatment or prevention of central nervous systemdisorders including the group consisting of schizophrenia; refractory,intractable or chronic schizophrenia; emotional disturbance; psychoticdisorder; mood disorder; bipolar disorder (for example, bipolar I typedisorder and bipolar II type disorder); depression; endogenousdepression; major depression; melancholy and refractory depression;dysthymic disorder; cyclothymic disorder; anxiety disorder (for example,panic attack, panic disorder, agoraphobia, social phobia,obsessive-compulsive disorder, post-traumatic stress disorder,generalized anxiety disorder, acute stress disorder, etc.); somatoformdisorder (for example, hysteria, somatization disorder, conversiondisorder, pain disorder, hypochondriasis, etc.); factitious disorder;dissociative disorder; sexual disorder (for example, sexual dysfunction,sexual desire disorder, sexual arousal disorder, erectile dysfunction,etc.); eating disorder (for example, anorexia nervosa, bulimia nervosa,etc.); sleep disorder; adjustment disorder; substance-related disorder(for example, alcohol abuse, alcohol intoxication, drug addiction,stimulant intoxication, narcotism, etc.); anhedonia (for example,iatrogenic anhedonia, anhedonia of a psychic or mental cause, anhedoniaassociated with depression, anhedonia associated with schizophrenia,etc.); delirium; cognitive impairment; cognitive impairment associatedwith Alzheimer's disease, Parkinson's disease, and otherneurodegenerative diseases; cognitive impairment caused by Alzheimer'sdisease, Parkinson's disease and associated neurodegenerative diseases;cognitive impairment of schizophrenia; cognitive impairment caused byrefractory, intractable or chronic schizophrenia; vomiting; motionsickness; obesity; migraine; pain (ache); mental retardation; autismdisorder (autism); Tourette's disorder; tic disorder;attention-deficit/hyperactivity disorder; conduct disorder; and Down'ssyndrome.

Furthermore, the compounds of the present invention have little or noside effects and they are excellent in safety and tolerability.

EXAMPLES

Hereinbelow, the present invention will be further made clear withreference to Reference Examples, Examples, Pharmacological Test Examplesand Preparation Examples.

Reference Example 1 Preparation of 7-(4-chlorobutoxy)-1H-quinolin-2-one

After 14.7 g of potassium hydroxide was added to a methanol (250 ml)suspension of 30 g of 7-hydroxy-1H-quinolin-2-one, which was stirred at50° C. to form a solution, 65 ml of 1-bromo-4-chlorobutane was addedthereto and refluxed for 8 hours. After cooling to room temperature,precipitated crystals were separated by filtration. They were purifiedby silica gel column chromatography (dichloromethane:methanol=100:3),and 29.6 g of 7-(4-chlorobutoxy)-1H-quinolin-2-one was obtained in theform of a white powder.

¹H-NMR (CDCl₃) δ ppm:

1.95-2.15 (4H, m), 3.60-3.70 (2H, m), 4.10 (2H, t, J=5.6 Hz), 6.56 (1H,dd, J=9.0 Hz, 3.8 Hz), 6.81 (1H, dd, J=8.7 Hz, 2.4 Hz), 6.85 (1H, d,J=2.3 Hz), 7.45 (1H, d, J=8.7 Hz), 7.75 (1H, d, J=9.4 Hz), 12.54 (1H,brs).

Reference Example 2 Preparation of7-(4-chlorobutoxy)-4-methyl-1H-quinolin-2-one

7-(4-chlorobutoxy)-4-methyl-1H-quinolin-2-one was prepared from7-hydroxy-4-methyl-1H-quinolin-2-one by a similar method as in ReferenceExample 1.

White powder

¹H-NMR (DMSO-d₆) δ ppm:

1.80-2.00 (4H, m), 2.37 (3H, s), 3.72 (2H, t, J=6.0 Hz), 4.05 (2H, t,J=6.0 Hz), 6.20 (1H, s), 6.75-6.90 (2H, m), 7.60 (1H, d, J=8.5 Hz),11.42 (1H, brs).

Reference Example 3 Preparation of 7-methoxy-3-methyl-1H-quinolin-2-one

30.7 ml of triethylsilane was added to a trifluoroacetic acid (300 ml)solution of 13 g of 7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehydewhile being stirred under ice-cooling and stirred at room temperatureovernight. The reaction solution was poured into ice water and extractedwith dichloromethane and, after washed with water, dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(dichloromethane:methanol=30:1), and 11.1 g of7-methoxy-3-methyl-1H-quinolin-2-one was obtained in the form of a whitepowder.

¹H-NMR (DMSO-d₆) δ ppm:

2.02 (3H, s), 3.77 (3H, s), 6.70-6.80 (2H, m), 7.45 (1H, d, J=8.4 Hz),7.64 (1H, s), 11.56 (1H, brs).

Reference Example 4 Preparation of 7-hydroxy-3-methyl-H-quinolin-2-one

47% hydrobromic acid (60 ml) suspension of 2.12 g of7-methoxy-3-methyl-1H-quinolin-2-one was refluxed for six hours. Aftercooling, water was added to the reaction solution and precipitatedcrystals were separated by filtration. The crystals were dissolved in amixed solvent of dichloromethane and methanol and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure and 1.7 gof 7-hydroxy-3-methyl-1H-quinolin-2-one was obtained in the form of abrown powder.

¹H-NMR (DMSO-d₆) δ ppm:

1.99 (3H, s), 6.57 (1H, dd, J=8.5 Hz, 2.5 Hz), 6.65 (1H, d, J=2.5 Hz),7.34 (1H, d, J=8.5 Hz), 7.58 (1H, s), 9.90 (1H, s), 11.48 (1H, brs).

Reference Example 5 Preparation of7-(3-chloropropoxy)-3-methyl-1H-quinolin-2-one

By a similar method as in Reference Example 1,7-(3-chloropropoxy)-3-methyl-1H-quinolin-2-one in the form of a whitepowder was prepared from 7-hydroxy-3-methyl-1H-quinolin-2-one using1-bromo-3-chloropropane.

¹H-NMR (DMSO-d₆) δppm:

2.05 (3H, s), 2.15-2.25 (2H, m), 3.81 (2H, t, J=6.5 Hz), 4.11 (2H, t,J=6.0 Hz), 6.75-6.85 (2H, m), 7.48 (1H, d, J=8.5 Hz), 7.67 (1H, s),11.59 (1H, brs).

Reference Example 6 Preparation of7-(4-chlorobutoxy)-3-methyl-1H-quinolin-2-one

By a similar method as in Reference Example 1,7-(4-chlorobutoxy)-3-methyl-1H-quinolin-2-one in the form of a whitepowder was prepared from 7-hydroxy-3-methyl-1H-quinolin-2-one using1-bromo-4-chlorobutane.

¹H-NMR (DMSO-d₆) δ ppm:

1.80-1.95 (4H, m), 2.04 (3H, s), 3.72 (2H, t, J=6.0 Hz), 4.03 (2H, t,J=6.0 Hz), 6.75-6.80 (2H, m), 7.47 (1H, d, J=8.5 Hz), 7.66 (1H, s),11.58 (1H, brs).

Reference Example 7 Preparation of 1-(4-chlorobutyl)-1H-quinolin-2-one

0.30 g of sodium hydride (60% oily) was added to a dimethylformamide (20ml) solution of 1.0 g of 1H-quinolin-2-one while being stirred underice-cooling and stirred at room temperature for 0.5 hour, and after that1.6 ml of 1-bromo-4-chlorobutane was added and stirred at roomtemperature for 14 hours. Water was added to the reaction solution,which was then extracted with ethyl acetate and, after washed withwater, dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1), and 1.02 g of1-(4-chlorobutyl)-1H-quinolin-2-one was obtained in the form ofcolorless oil.

¹H-NMR (CDCl₃) δ ppm:

1.85-2.00 (4H, m), 3.60-3.65 (2H, m), 4.35 (2H, t, J=7.0 Hz), 6.70 (1H,d, J=9.5 Hz), 7.23 (1H, dd, J=8.6 Hz, 7.5 Hz), 7.38 (1H, d, J=8.9 Hz),7.54-7.62 (2H, m), 7.68 (1H, d, J=9.5 Hz).

Reference Example 8 Preparation of 1-(5-chloropentyl)-1H-quinolin-2-one

By a similar method as in Reference Example 7,1-(5-chloropentyl)-1H-quinolin-2-one in the form of colorless oil wasprepared from 1H-quinolin-2-one using 1-bromo-5-chloropentane.

¹H-NMR (CDCl₃) δ ppm:

1.55-1.70 (2H, m), 1.75-1.95 (4H, m), 3.56 (2H, t, J=6.6 Hz), 4.31 (2H,t, J=7.8 Hz), 6.70 (1H, d, J=9.5 Hz), 7.23 (1H, dd, J=7.3 Hz, 7.3 Hz),7.35 (1H, d, J=8.9 Hz), 7.54-7.60 (2H, m), 7.67 (1H, d, J=9.4 Hz).

Reference Example 9 Preparation of7-(4-chloro-(Z)-2-butenyloxy)-3,4-dihydro-1H-quinolin-2-one

A mixture of 1.0 g of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 1.7 g ofpotassium carbonate, 3.2 ml of cis-1,4-dichloro-2-butene and 50 ml ofdimethylformamide was stirred at room temperature overnight. Water wasadded to the reaction solution, which was then extracted with ethylacetate and, after washed with water, dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=3:1), and7-(4-chloro-(Z)-2-butenyloxy)-3,4-dihydro-1H-quinolin-2-one (1.3 g) wasobtained in the form of a white powder.

¹H-NMR (CDCl₃) δ ppm:

2.62 (2H, t, J=6.3 Hz), 2.90 (2H, t, J=6.3 Hz), 4.16 (2H, d, J=6.3 Hz),4.62 (2H, d, J=4.6 Hz), 5.86-5.90 (2H, m), 6.31 (1H, d, J=2.5 Hz), 6.54(1H, dd, J=8.3 Hz, 2.5 Hz), 7.06 (1H, d, J=8.3 Hz), 7.56 (1H, brs).

Reference Example 10 Preparation of2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyric acid methylester

4.98 g of sodium iodide was added to an acetonitrile (70 ml) solution of5 g of 4-chloro-2-methylbutyric acid methyl ester and it was refluxedfor 3 hours. Water was added to the reaction solution, which was thenextracted with dichloromethane and, after washed with water, dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was added to a mixture of 4.33 g of7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 6.0 g of potassium carbonateand dimethylformamide (90 ml) and stirred at 80° C. for 6 hours. Waterwas added to the reaction solution, which was then extracted with ethylacetate and, after washed with water, dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography(dichloromethane:methanol=100:3), and 6.0 g of2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyric acid methylester was obtained in the form of a yellow oil.

¹H-NMR (CDCl₃) δ ppm:

1.23 (3H, d, J=7.1 Hz), 1.75-1.90 (1H, m), 2.10-2.25 (1H, m), 2.55-2.65(2H, m), 2.72 (1H, q, J=7.0 Hz), 2.80-2.90 (2H, m), 3.68 (3H, s), 3.95(2H, t, J=6.2 Hz), 6.33 (1H, d, J=2.3 Hz), 6.49 (1H, dd, J=8.3 Hz, 2.21Hz), 7.02 (1H, d, J=8.3 Hz), 8.41 (1H, brs).

Reference Example 11 Preparation of7-(4-hydroxy-3-methylbutoxy)-3,4-dihydro-1H-quinolin-2-one

6 g of 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyric acidmethyl ester was added dropwise to a tetrahydrofuran (200 ml) suspensionof 1.6 g of lithium aluminum hydride while being stirred underice-cooling and stirred at the same temperature for 2 hours. While beingstirred under ice-cooling, saturated Rochelle salt aqueous solution wasadded, which was extracted with diethyl ether and, after washed withwater, dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (dichloromethane:methanol=40:1), and 2.8 g of7-(4-hydroxy-3-methylbutoxy)-3,4-dihydro-1H-quinolin-2-one was obtainedin the form of a yellow oil.

¹H-NMR (CDCl₃) δ ppm:

0.99 (3H, d, J=6.5 Hz), 1.60-2.05 (3H, m), 2.60-2.65 (2H, m), 2.85-2.95(2H, m), 3.55 (2H, t, J=5.3 Hz), 3.95-4.10 (2H, m), 6.38 (1H, d, J=2.5Hz), 6.53 (1H, dd, J=8.3 Hz, 2.4 Hz), 7.04 (1H, d, J=8.3 Hz), 8.59 (1H,brs).

Reference Example 12 Preparation of methanesulfonic acid2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl ester

Methanesulfonyl chloride (1.0 ml) was added to a dichloromethane (80 ml)solution of 2.8 g of 7-(4-hydroxy-3-methylbutoxy)-3,4-dihydro-1H-quinolin-2-one and 2.4 ml of triethylamine whilebeing stirred under ice-cooling and stirred at room temperatureovernight. Water was added to the reaction solution, which was thenextracted with dichloromethane and, after washed with water, dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(dichloromethane:methanol=30:1), and methanesulfonic acid2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl ester (2.8 g)was obtained in the form of a green powder.

¹H-NMR (CDCl₃) δ ppm:

1.07 (3H, d, J=6.8 Hz), 1.60-1.80 (1H, m), 1.90-2.00 (1H, m), 2.15-2.25(1H, m), 2.50-2.65 (2H, m), 2.90 (2H, t, J=7.3 Hz), 3.95-4.10 (2H, m),4.10-4.20 (2H, m), 6.33 (1H, d, J=2.5 Hz), 6.51 (1H, dd, J=8.3 Hz, 2.5Hz), 7.05 (1H, d, J=8.3 Hz), 8.16 (1H, brs).

Reference Example 13 Preparation of7-(4-bromo-(E)-2-butenyloxy)-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Reference Example 9,7-(4-bromo-(E)-2-butenyloxy)-3,4-dihydro-1H-quinolin-2-one in the formof a white powder was prepared from7-hydroxy-3,4-dihydro-1H-quinolin-2-one usingtrans-1,4-dibromo-2-butene.

¹H-NMR (CDCl₃) δ ppm:

2.61 (2H, t, J=7.5 Hz), 2.89 (2H, t, J=7.5 Hz), 3.98 (2H, d, J=7.0 Hz),4.51 (2H, d, J=4.8 Hz), 5.90-6.10 (2H, m), 6.43 (1H, d, J=2.1 Hz), 6.51(1H, dd, J=8.2 Hz, 2.1 Hz), 7.03 (1H, d, J=8.2 Hz), 9.35 (1H, brs).

Reference Example 14 Preparation of7-(4-chlorobutoxy)-4-methyl-3,4-dihydro-1H-quinolin-2-one

Boron tribromide (1 M dichloromethane solution, 6.2 ml) was added to adichloromethane solution (5 ml) of 0.54 g of7-methoxy-4-methyl-3,4-dihydro-1H-quinolin-2-one while being stirredunder ice-cooling and 0.23 g of precipitated crude crystals wereseparated by filtration. 0.2 g of potassium carbonate and 0.45 ml of1-bromo-4-chlorobutane were added to an acetonitrile (2.5 ml)-water (2.5ml) solution of the crude crystals and refluxed for 6 hours. Water wasadded to the reaction solution, which was then extracted with ethylacetate and, after washed with water, dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography(dichloromethane:methanol=50:1), and7-(4-chlorobutoxy)-4-methyl-3,4-dihydro-1H-quinolin-2-one (0.29 g) wasobtained in the form of a white powder.

¹H-NMR (DMSO-d₆) δ ppm:

1.28 (3H, d, J=7.0 Hz), 1.85-2.05 (4H, m), 2.35-2.45 (1H, m), 2.65-2.75(1H, m), 3.00-3.15 (1H, m), 3.62 (2H, t, J=6.0 Hz), 3.97 (2H, t, J=6.0Hz), 6.32 (1H, d, J=2.5 Hz), 6.55 (1H, dd, J=8.5 Hz, 2.5 Hz), 7.08 (1H,d, J=8.5 Hz), 7.96 (1H, brs).

Reference Example 15 Preparation of7-[2-(2-chloroethoxy)ethoxy]-3,4-dihydro-1H-quinolin-2-one

A mixture of 7.0 g of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 7.1 g ofpotassium carbonate, 30 ml of bis-2-chloroethyl ether and 400 ml ofacetonitrile was refluxed for 2 days. Water was added to the reactionsolution, which was then extracted with dichloromethane and, afterwashed with water, dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (dichloromethane:methanol=40:1), and 8.3 g of7-[2-(2-chloroethoxy)ethoxy]-3,4-dihydro-1H-quinolin-2-one was obtainedin the form of a white powder.

¹H-NMR (CDCl₃) δ ppm:

2.61 (2H, t, J=7.4 Hz), 2.90 (2H, t, J=7.4 Hz), 3.66 (2H, t, J=5.8 Hz),3.74-3.88 (4H, m), 4.11 (2H, t, J=4.7 Hz), 6.36 (1H, d, J=2.2 Hz), 6.54(1H, dd, J=8.3 Hz, 2.2 Hz), 7.05 (1H, d, J=8.3 Hz), 8.01 (1H, m).

Reference Example 16 Preparation of6-(3-chloropropoxy)-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Reference Example 9,6-(3-chloropropoxy)-3,4-dihydro-1H-quinolin-2-one in the form of a whitepowder was prepared from 6-hydroxy-3,4-dihydro-1H-quinolin-2-one using1-bromo-3-chloropropane.

¹H-NMR (CDCl₃) δppm:

2.15-2.35 (2H, m), 2.55-2.65 (2H, m), 2.90-3.00 (2H, m), 3.50-3.80 (2H,m), 4.00-4.10 (2H, m), 6.73 (3H, brs), 8.68 (1H, brs).

Reference Example 17 Preparation of6-(4-bromobutoxy)-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Reference Example 9,6-(4-bromobutoxy)-3,4-dihydro-1H-quinolin-2-one in the form of a whitepowder was prepared from 6-hydroxy-3,4-dihydro-1H-quinolin-2-one using1,4-dibromobutane.

¹H-NMR (DMSO-d₆) δppm:

1.75-1.85 (2H, m), 1.90-2.00 (2H, m), 2.30-2.45 (2H, m), 2.75-2.85 (2H,m), 3.58 (2H, t, J=6.5 Hz), 3.91 (2H, t, J=6.5 Hz), 6.70-6.80 (3H, m),9.88 (1H, brs).

Reference Example 18 Preparation of1-(5-chloropentyl)-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Reference Example 7, 1-(5-chloropentyl)-3,4-dihydro-1H-quinolin-2-one in the form of colorless oil was preparedfrom 3,4-dihydro-1H-quinolin-2-one using 1-bromo-5-chloropentane.

¹H-NMR (CDCl₃) δ ppm:

1.45-1.60 (2H, m), 1.60-1.75 (2H, m), 1.75-1.90 (2H, m), 2.60-2.70 (2H,m), 2.85-2.95 (2H, m), 3.54 (2H, d, J=6.6 Hz), 3.59 (2H, d, J=7.7 Hz),6.76-7.04 (2H, m), 7.15-7.29 (2H, m).

Reference Example 19 Preparation of2-(5-chloropentyl)-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Reference Example 7,2-(5-chloropentyl)-3,4-dihydro-2H-isoquinolin-1-one in the form of brownoil was prepared from 3,4-dihydro-2H-isoquinolin-1-one using1-bromo-5-chloropentane.

¹H-NMR (CDCl₃) δ ppm:

1.50-2.00 (6H, m), 2.99 (2H, t, J=6.6 Hz), 3.52-3.60 (6H, m), 7.17 (1H,d, J=7.3 Hz), 7.31-7.44 (2H, m), 8.07 (1H, dd, J=1.3 Hz, 7.5 Hz).

Reference Example 20 Preparation of7-(3-chloropropoxy)-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Reference Example 9,7-(3-chloropropoxy)-3,4-dihydro-2H-isoquinolin-1-one in the form ofbrown oil was prepared from 7-hydroxy-3,4-dihydro-2H-isoquinolin-1-oneusing 1-bromo-3-chloropropane.

¹H-NMR (CDCl₃) δ ppm:

2.20-2.40 (2H, m), 2.90-3.00 (2H, m), 3.50-3.80 (4H, m), 4.15-4.20 (4H,m), 6.48 (1H, brs), 7.01 (1H, dd, J=4.0 Hz, 1.5 Hz), 7.13 (1H, d, J=4.0Hz), 7.59 (1H, d, J=1.4 Hz).

Reference Example 21 Preparation of7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Reference Example 4,7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one in the form of abrown powder was prepared from7-methoxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one.

¹H-NMR (DMSO-d₆) δppm:

2.84 (2H, t, J=6.5 Hz), 3.01 (3H, s), 3.47 (2H, t, J=6.6 Hz), 6.85 (1H,dd, J=8.1 Hz, 2.5 Hz), 7.08 (1H, d, J=8.1 Hz), 7.29 (1H, d, J=2.5 Hz),9.49 (1H, s).

Reference Example 22 Preparation of7-(4-chlorobutoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Reference Example 9,7-(4-chlorobutoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one in the formof a brown oil was prepared from7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one using1-bromo-4-chlorobutane.

¹H-NMR (CDCl₃) δ ppm:

1.90-2.00 (4H, m), 2.93 (2H, t, J=6.8 Hz), 3.15 (3H, s), 3.45-3.65 (4H,m), 4.04 (2H, t, J=5.8 Hz), 6.95 (1H, dd, J=8.3 Hz, 2.5 Hz), 7.07 (1H,d, J=8.3 Hz), 7.59 (1H, d, J=2.5 Hz).

Reference Example 23 Preparation of7-(4-chlorobutoxy)-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Reference Example 9,7-(4-chlorobutoxy)-3,4-dihydro-2H-isoquinolin-1-one in the form of awhite powder was prepared from7-hydroxy-3,4-dihydro-2H-isoquinolin-1-one using 1-bromo-4-chlorobutane.

¹H-NMR (CDCl₃) δ ppm:

1.93-2.00 (4H, m), 2.88-2.96 (2H, m), 3.51-3.58 (2H, m), 3.62 (2H, t,J=6.2 Hz), 4.05 (2H, t, J=5.7 Hz), 6.25 (1H, s), 7.00 (1H, dd, J=8.3 Hz,2.7 Hz), 7.13 (1H, d, J=8.3 Hz), 7.57 (1H, d, J=2.7 Hz).

Reference Example 24 Preparation of2-(4-chlorobutyl)-2H-isoquinolin-1-one

By a similar method as in Reference Example 7,2-(4-chlorobutyl)-2H-isoquinolin-1-one in the form of a yellow oil wasprepared from 2H-isoquinolin-1-one using 1-bromo-4-chlorobutane.

¹H-NMR (CDCl₃) δ ppm:

1.80-2.00 (4H, m), 3.59 (2H, t, J=6.3 Hz), 4.05 (2H, t, J=7.0 Hz), 6.51(1H, d, J=7.4 Hz), 7.05 (1H, d, J=7.4 Hz), 7.46-7.52 (2H, m), 7.63 (1H,m), 8.42 (1H, d, J=8.1 Hz).

Reference Example 25 Preparation of7-(3-chloropropoxy)-2H-isoquinolin-1-one

By a similar method as in Reference Example 9,7-(3-chloropropoxy)-2H-isoquinolin-1-one in the form of a white powderwas prepared from 7-hydroxy-2H-isoquinolin-1-one using1-bromo-3-chloropropane.

¹H-NMR (CDCl₃) δ ppm:

2.30 (2H, quint, J=6.1 Hz), 3.78 (2H, t, J=6.4 Hz), 4.28 (2H, t, J=5.9Hz), 6.54 (1H, d, J=7.1 Hz), 7.06 (1H, d, J=6.6 Hz), 7.29 (1H, dd, J=8.7Hz, 2.7 Hz), 7.51 (1H, d, J=8.7 Hz), 7.82 (1H, d, J=2.7 Hz), 10.64 (1H,s).

Reference Example 26 Preparation of7-(3-chloropropoxy)-2-ethyl-2H-isoquinolin-1-one

By a similar method as in Reference Example 7,7-(3-chloropropoxy)-2-ethyl-2H-isoquinolin-1-one in the form of acolorless oil was prepared from 7-(3-chloropropoxy)-2H-isoquinolin-1-oneusing ethyl iodide.

¹H-NMR (CDCl₃) δ ppm:

1.38 (3H, t, J=7.2 Hz), 2.29 (2H, quint, J=6.1 Hz), 3.76 (2H, t, J=6.4Hz), 4.07 (2H, q, J=7.2 Hz), 4.25 (2H, d, J=5.8 Hz), 6.48 (1H, d, J=7.3Hz), 6.98 (1H, d, J=7.3 Hz), 7.23 (1H, dd, J=8.7 Hz, 2.7 Hz), 7.44 (1H,d, J=8.7 Hz), 7.85 (1H, d, J=2.6 Hz).

Reference Example 27 Preparation of2-(4-chlorobutyl)-7-methoxy-2H-isoquinolin-1-one

By a similar method as in Reference Example 7,2-(4-chlorobutyl)-7-methoxy-2H-isoquinolin-1-one in the form ofcolorless oil was prepared from 7-methoxy-2H-isoquinolin-1-one using1-bromo-4-chlorobutane.

¹H-NMR (CDC₃) δppm:

1.64-2.00 (4H, m), 3.59 (2H, t, J=6.3 Hz), 3.93 (3H, s), 4.06 (2H, t,J=6.9 Hz), 6.49 (1H, d, J=7.3 Hz), 6.96 (1H, d, J=7.3 Hz), 7.25 (1H, dd,J=8.6 Hz, 2.7 Hz), 7.45 (1H, d, J=8.7 Hz), 7.83 (1H, d, J=2.7 Hz).

Reference Example 28 Preparation of6-(3-chloropropoxy)-2H-isoquinolin-1-one

By a similar method as in Reference Example 9,6-(3-chloropropoxy)-2H-isoquinolin-1-one in the form of a pale yellowpowder was prepared from 6-hydroxy-2H-isoquinolin-1-one using1-bromo-3-chloropropane.

¹H-NMR (CDCl₃) δppm:

2.30 (2H, quint, J=6.0 Hz), 3.78 (2H, t, J=6.2 Hz), 4.24 (2H, t, J=5.9Hz), 6.46 (1H, d, J=7.2 Hz), 6.93 (1H, d, J=2.4 Hz), 7.05-7.12 (2H, m),8.33 (1H, d, J=8.9 Hz), 10.33 (1H, s).

Reference Example 29 Preparation of7-(3-chloropropoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Reference Example 9,7-(3-chloropropoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one in theform of a brown powder was prepared from7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one using1-bromo-3-chloropropane.

¹H-NMR (CDCl₃) δppm:

2.15-2.35 (2H, m), 2.85-3.00 (2H, m), 3.15 (3H, s), 3.50-3.80 (4H, m),4.10-4.20 (2H, m), 6.96 (1H, dd, J=8.3 Hz, 2.7 Hz), 7.08 (1H, d, J=8.3Hz), 7.62 (1H, d, J=2.7 Hz).

Reference Example 30 Preparation of 1-benzo[b]thiophen-4-yl-piperazinehydrochloride

A mixture of 14.4 g of 4-bromobenzo[b]thiophene, 29.8 g of piperazineanhydride, 9.3 g of sodium t-butoxide, 0.65 g of(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 0.63 g ofdipalladium tris(dibenzylideneacetone) and 250 ml of toluene wasrefluxed for 1 hour under nitrogen atmosphere. Water was poured to thereaction solution, which was then extracted with ethyl acetate and,after washed with water, dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (dichloromethane:methanol:25% ammoniawater=100:10:1), and 9.5 g of 1-benzo[b]thiophen-4-yl-piperazine in theform of yellow oil was obtained.

3.7 ml of concentrated hydrochloric acid was added to a methanolsolution of 9.5 g of 1-benzo[b]thiophen-4-yl-piperazine, and the solventwas evaporated under reduced pressure. Ethyl acetate was added to theresidue and precipitated crystals were filtrated and recrystallized frommethanol and 1-benzo[b]thiophen-4-yl-piperazine hydrochloride wasobtained as colorless needle-like crystals.

Melting point 276-280° C.

¹H-NMR (DMSO-ds) δppm:

3.25-3.35 (8H, m), 6.94 (1H, d, J=7.6 Hz), 7.30 (1H, dd, J=7.8 Hz, 7.8Hz), 7.51 (1H, d, J=5.5 Hz), 7.68 (1H, d, J=8.1 Hz), 7.73 (1H, d, J=5.5Hz), 9.35 (2H, brs).

Reference Example 31 Preparation of tert-butyl4-benzo[b]thiophen-4-yl-3-methylpiperazin-1-carboxylate

In the same manner as in Reference Example 30, tert-butyl4-benzo[b]thiophen-4-yl-3-methylpiperazin-1-carboxylate was preparedfrom tert-butyl 3-methylpiperazin-1-carboxylate and4-bromobenzo[b]thiophene.

¹H-NMR (CDCl₃) δ ppm:

1.85-1.95 (3H, m), 1.50 (9H, s), 2.8-2.9 (1H, m), 3.15-3.35 (2H, m),3.4-3.5 (1H, m), 3.5-3.65 (1H, m), 3.65-3.7 (1H, m), 3.7-3.9 (1H, m),6.98 (1H, d, J=7.5 Hz), 7.29 (1H, dd, J=8, 8 Hz), 7.38 (1H, d, J=5.5Hz), 7.61 (1H, d, J=8 Hz).

Reference Example 32 Preparation of1-benzo[b]thiophen-4-yl-2-methylpiperazine dihydrochloride

A solution of 1.22 g (3.7 mmol) of tert-butyl4-benzo[b]thiophen-4-yl-3-methylpiperazin-1-carboxylate in methylenechloride (12 ml) was added to trifluoroacetic acid (6 ml), and themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, then an aqueous solution of 5%potassium carbonate was added to the residue and the resulting mixturewas extracted with methylene chloride. The organic phase was dried overmagnesium sulfate and concentrated under reduced pressure. Concentratedhydrochloric acid (6 ml) and methanol (10 ml) were added to the residueand the resulting mixture was concentrated under reduced pressure. Theresidue was recrystallized from acetonitrile to obtain1-benzo[b]thiophen-4-yl-2-methylpiperazine dihydrochloride (0.98 g) aslight brown powder.

¹H-NMR (DMSO-d₆) δ ppm:

0.92 (3H, d, J=6.5 Hz), 2.8-3.6 (6H, m), 3.6-4.0 (1H, m), 5.3-6.8 (1H,m), 7.20 (1H, br), 7.38 (1H, dd, J=8, 8 Hz), 7.5-8.0 (3H, m), 9.4-10.1(2H, m).

Reference Example 33 Preparation of1-benzo[b]thiophen-4-yl-3-methylpiperazine dihydrochloride

In the same manner as in Reference Example 30,1-benzo[b]thiophen-4-yl-3-methylpiperazine dihydrochloride was preparedfrom 2-methylpiperazine and 4-bromobenzo[b]thiophene.

¹H-NMR (DMSO-d₆) δ ppm:

1.34 (3H, d, J=6.5 Hz), 2.85-2.95 (1H, m), 3.05-3.15 (1H, m), 3.2-3.6(6H, m), 6.97 (1H, d, J=7.5 Hz), 7.31 (1H, dd, J=8, 8 Hz), 7.54 (1H, d,J=5.5 Hz), 7.69 (1H, d, J=8 Hz), 7.75 (18, d, J=5.5 Hz), 9.2-9.3 (1H,m), 9.64 (1H, br).

Reference Example 34 Preparation of ethyl3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate

5.05 g (19.8 mmol) of l-Benzo[b]thiophen-4-yl-piperazine hydrochloridewas added to an aqueous solution of sodium hydroxide, and the mixturewas extracted with methylene chloride. The organic phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in 50 ml of ethanol and ethyl acrylate (2.44 ml, 21.8mmol) was added thereto, then the reaction mixture was refluxed for 4hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. Isopropyl ether was added to theresidue to filter out insoluble matters. The insoluble matters werewashed with isopropyl ether and dried to obtain ethyl3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate (5.26 g) as whitepowder.

Reference Example 35 Preparation of3-(4-benzo[b]thiophen-4-yl-piperazine-1-yl)propan-1-ol

Lithium aluminum hydride (1.18 g, 24.8 mmol) was added to a solution of5.26 g (16.5 mmol) of ethyl3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate in tetrahydrofuran(55 ml) with cooling in an ice-bath, followed by stirring at roomtemperature for 4 hours. Water (1.2 ml), 15% sodium hydroxide aqueoussolution (1.2 ml), and water (3.6 ml) were added to the reaction mixturein this order with stirring at room temperature. Insoluble matters wereremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane: ethyl acetate=3:2→ethyl acetate), then concentrated and driedunder reduced pressure to obtain3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propane-1-ol (0.23 g) as whitepowder.

¹H-NMR (CDCl₃) δ ppm:

1.75-1.85 (2H, m), 2.74 (2H, t, J=5.8 Hz), 2.75-2.85 (4H, m), 3.15-3.25(4H, m), 3.85 (2H, t, J=5.3 Hz), 5.19 (1H, brs), 6.88 (1H, d, J=7.6 Hz),7.27 (1H, dd, J=7.9, 7.8 Hz), 7.39 (2H, s), 7.56 (1H, d, J=8.0 Hz).

Reference Example 36 Preparation of4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate

1.0 g (3.9 mmol) of 1-Benzo[b]thiophen-4-yl-piperazine hydrochloride wassuspended in 20 ml of dimethylformamide (DMF), and potassium carbonate(1.3 g, 9.4 mmol) and 4-bromobutyl acetate (0.7 ml, 4.8 mmol) were addedthereto followed by stirring at 80° C. for 6 hours. The reaction mixturewas cooled to room temperature, then water was added thereto and theresulting mixture was extracted with ethyl acetate. The organic phasewas washed with water, dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (methylene chloride:methanol=30:1), then concentratedunder reduced pressure to obtain4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate (0.72 g) aslight yellow oil.

Reference Example 37 Preparation of4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butan-1-ol

Potassium carbonate (3.87 g, 28 mmol) was added to a solution of 7.76 g(23.3 mmol) of butyl 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)acetatein 90% methanol (150 ml) followed by stirring at room temperature for 2hours. Water was added thereto and the reaction mixture was extractedwith methylene chloride. The organic phase was dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane: ethylacetate=2:1→1:1), then concentrated under reduced pressure to obtain4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butane-1-ol (6.65 g) ascolorless oil.

Reference Example 38 Preparation of1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine

3.56 g (12.9 mmol) of3-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol was suspended in30 ml of methylene chloride, and carbon tetrachloride (30 ml) andtriphenyl phosphine (4.06 g, 15.5 mmol) were added thereto followed bystirring under reflux for 3 hours. The reaction mixture was cooled toroom temperature, then methanol and methylene chloride were addedthereto so as to make the mixture uniform. Silica gel (30 g) was addedto the uniform solution, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(silica gel: 300 g, n-hexane: ethyl acetate=2:1), then concentratedunder reduced pressure to obtain1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine (2.36 g) ascolorless oil.

¹H-NMR (CDCl₃) δ ppm:

1.95-2.10 (2H, m), 2.60 (2H, t, J=7.2 Hz), 2.65-2.75 (4H, m), 3.15-3.25(4H, m), 3.65 (2H, t, J=6.6 Hz), 6.89 (1H, dd, J=7.6, 0.7 Hz), 7.27 (1H,dd, J=7.9, 7.8 Hz), 7.38 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=5.7 Hz), 7.55(1H, d, J=8.0 Hz)

Example 1 Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one

A mixture of 9.0 g of 7-(4-chlorobutoxy)-1H-quinolin-2-one, 10 g of1-benzo[b]thiophene-4-yl-piperazine hydrochloride, 14 g of potassiumcarbonate, 6 g of sodium iodide and 90 ml of dimethylformamide wasstirred for 2 hours at 80° C. Water was added to the reaction solutionand precipitated crystals were separated by filtration. The crystalswere dissolved in a mixed solvent of dichloromethane and methanol, driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(dichloromethane:methanol=100:3). Recrystallized from ethanol, 13.6 g of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onein the form of a white powder was obtained.

Melting point 183.5-184.5° C.

¹H-NMR (DMSO-d₆) δppm:

1.6-1.75 (2H, m), 1.75-1.9 (2H, m), 2.44 (2H, t, J=7 Hz), 2.5-2.8 (4H,m), 2.9-3.2 (4H, m), 4.06 (2H, t, J=6.5 Hz), 6.30 (1H, d, J=9.5 Hz),6.75-6.85 (2H, m), 6.88 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=BHz, 8 Hz),7.40 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=9.5 Hz), 7.61 (1H, d, J=8 Hz),7.69 (1H, d, J=5.5 Hz), 7.80 (1H, d, J=9.5 Hz), 11.59 (1H, bs).

Example 2 Preparation of 3-[2-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)ethoxy]-1H-quinolin-2-one

By a similar method as in Example 1,3-[2-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)ethoxy]-H-quinolin-2-onewas prepared from 3-(2-bromoethoxy)-1H-quinolin-2-one.

White powder (chloroform)

Melting point 201.9-204.5° C.

¹H-NMR (CDCl₃) δppm:

2.90-2.95 (4H, m), 3.10 (2H, t, J=5.9 Hz), 3.23-3.27 (4H, m), 4.30 (2H,t, J=5.9 Hz), 6.90 (1H, d, J=7.7 Hz), 7.08 (1H, s), 7.15-7.32 (2H, m),7.37-7.41 (4H, m), 7.47-7.49 (1H, m), 7.55 (1H, d, J=8.1 Hz), 11.33 (1H,br).

Example 3 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-4-methyl-1H-quinolin-2-one

By a similar method as in Example 1,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-4-methyl-1H-quinolin-2-onewas prepared from 7-(3-chloropropoxy)-4-methyl-1H-quinolin-2-one.

Slightly brown powder (ethyl acetate)

Melting point 202-208° C.

¹H-NMR (DMSO-d₆) δppm:

1.95-2.0 (2H, m), 2.37 (3H, s), 2.55 (2H, t, J=7 Hz), 2.6-2.7 (4H, m),3.05-3.2 (4H, m), 4.09 (2H, t, J=6.5 Hz), 6.21 (1H, bs), 6.8-6.85 (2H,m), 6.90 (1H, d, J=7.5 Hz), 7.28 (1H, dd, J=8 Hz, 8 Hz), 7.41 (1H, d,J=5.5 Hz), 7.6-7.7 (2H, m), 7.69 (1H, d, J=5.5 Hz), 11.41 (1H, bs).

Example 4 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-4-methyl-1H-quinolin-2-one

By a similar method as in Example 1,7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-4-methyl-1H-quinolin-2-onewas prepared from 7-(4-chlorobutoxy)-4-methyl-1H-quinolin-2-one.

White powder (ethyl acetate)

Melting point 164-168° C.

¹H-NMR (DMSO-d₆) δppm:

1.6-1.7 (2H, m), 1.75-1.85 (2H, m), 2.37 (3H, s), 2.44 (2H, t, J=7 Hz),2.55-2.7 (4H, m), 3.0-3.2 (4H, m), 4.0-4.15 (2H, m), 6.20 (1H, bs),6.8-6.85 (2H, m), 6.88 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=8 Hz, 8 Hz),7.40 (1H, d, J=5.5 Hz), 7.6-7.7 (2H, m), 7.69 (1H, d, J=5.5 Hz), 11.42(1H, bs).

Example 5 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methyl-1H-quinolin-2-one

By a similar method as in Example 1,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methyl-1H-quinolin-2-onewas prepared from 7-(3-chloropropoxy)-3-methyl-1H-quinolin-2-one.

White powder (ethyl acetate)

Melting point 185-187° C.

¹H-NMR (DMSO-d₆) δppm:

1.9-2.0 (2H, m), 2.04 (3H, s), 2.55 (2H, t, J=7 Hz), 2.6-2.75 (4H, m),3.0-3.2 (4H, m), 4.07 (2H, t, J=6.5 Hz), 6.75-6.85 (2H, m), 6.90 (1H, d,J=7.5 Hz), 7.28 (1H, dd, J=8 Hz, 8 Hz), 7.40 (1H, d, J=5.5 Hz), 7.48(1H, d, J=8.5 Hz), 7.61 (1H, d, J=8 Hz), 7.65-7.7 (2H, m), 11.57 (1H,bs).

Example 6 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3-methyl-1H-quinolin-2-one

By a similar method as in Example 1,7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3-methyl-1H-quinolin-2-onewas prepared from 7-(4-chlorobutoxy)-3-methyl-1H-quinolin-2-one.

White powder (ethyl acetate)

Melting point 197-199° C.

¹H-NMR (DMSO-d₆) δppm:

1.6-1.7 (2H, m), 1.75-1.9 (2H, m), 2.04 (3H, s), 2.44 (2H, t, J=7 Hz),2.55-2.7 (4H, m), 3.0-3.15 (4H, m), 4.04 (2H, t, J=6.5 Hz), 6.75-6.85(2H, m), 6.88 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=8 Hz, 8 Hz), 7.40 (1H,d, J=5.5 Hz), 7.47 (1H, d, J=8.5 Hz), 7.61 (1H, d, J=8 Hz), 7.65-7.75(2H, m), 11.59 (1H, bs).

Example 7 Preparation of 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-quinolin-2-one

By a similar method as in Example 1,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-quinolin-2-onewas prepared from 7-(3-chloropropoxy)-1H-quinolin-2-one.

White powder (ethyl acetate-diethyl ether)

Melting point 204-207° C.

¹H-NMR (DMSO-d₆) δppm:

1.97 (2H, t, J=6.8 Hz), 2.50-2.60 (2H, m), 2.60-2.65 (4H, m), 3.05-3.10(4H, m), 4.08 (2H, t, J=6.4 Hz), 6.29 (1H, d, J=9.5 Hz), 6.75-6.85 (2H,m), 6.90 (1H, d, J=7.7 Hz), 7.25-7.30 (1H, m), 7.40 (1H, d, J=5.6 Hz),7.55 (1H, d, J=8.4 Hz), 7.60-7.65 (1H, m), 7.69 (1H, d, J=5.5 Hz), 7.80(1H, d, J=9.5 Hz), 11.57 (1H, s).

Example 8 Preparation of1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-1H-quinolin-2-onehydrochloride

By a similar method as in Example 1,1-[4-1-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-1H-quinolin-2-onewas prepared from 1-(4-chlorobutyl)-1H-quinolin-2-one, and after it wasmade into an ethanol solution, 1N hydrochloric acid ethanol solution wasadded thereto, precipitated crystals were separated by filtration, andthereby1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-1H-quinolin-2-onehydrochloride was obtained in the form of a white powder.

Melting point 282.0° C. (decomposed)

¹H-NMR (DMSO-d₆) δppm:

1.60-2.00 (4H, m), 3.10-3.40 (6H, m), 3.50-3.60 (4H, m), 4.31 (2H, t,J=7.4 Hz), 6.63 (1H, d, J=9.4 Hz), 6.96 (1H, d, J=7.6 Hz), 7.24-7.35(2H, m), 7.48 (1H, d, J=5.4 Hz), 7.59-7.78 (5H, m), 7.93 (1H, d, J=9.5Hz), 10.00-10.20 (1H, m).

Example 9 Preparation of1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)pentyl]-1H-quinolin-2-onehydrochloride

By a similar method as in Example 1,1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)pentyl]-H-quinolin-2-onewas prepared from 1-(5-chloropentyl)-1H-quinolin-2-one, and after it wasmade into an ethanol solution, 1N hydrochloric acid ethanol solution wasadded thereto, precipitated crystals were separated by filtration, andthereby1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)pentyl]-1H-quinolin-2-onehydrochloride was obtained in the form of a white powder.

Melting point 225.0-227.0° C.

¹H-NMR (DMSO-d₆) δ ppm:

1.35-1.50 (2H, m), 1.60-1.80 (4H, m), 3.10-3.30 (6H, m), 3.50-3.60 (4H,m), 4.27 (2H, t, J=7.4 Hz), 6.61 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=7.5Hz), 7.20-7.34 (2H, m), 7.47 (1H, d, J=5.5 Hz), 7.61-7.77 (5H, m), 7.91(1H, d, J=9.5 Hz), 10.30-10.50 (1H, m).

Example 10 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Example 1,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-onewas prepared from 7-(3-chloropropoxy)-3,4-dihydro-1H-quinolin-2-one.

White powder (methanol)

Melting point 163-165° C.

¹H-NMR (DMSO-d₆) δppm:

1.8-2.0 (2H, m), 2.41 (2H, t, J=7.5 Hz), 2.45-2.6 (2H, m), 2.6-2.7 (4H,m), 2.78 (2H, t, J=7.5 Hz), 2.95-3.2 (4H, m), 3.97 (2H, t, J=6.3 Hz),6.46 (1H, d, J=2.3 Hz), 6.50 (1H, dd, J=2.4 Hz, 8.2 Hz), 6.90 (1H, d,J=7.6 Hz), 7.04 (1H, d, J=8.2 Hz), 7.27 (1H, dd, J=7.8 Hz, 7.8 Hz), 7.40(1H, d, J=5.6 Hz), 7.61 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=5.5 Hz), 9.97(1H, bs).

Example 11 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Example 1,7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-onewas prepared from 7-(4-chlorobutoxy)-3,4-dihydro-1H-quinolin-2-one.

White powder (methanol)

Melting point 147-148° C.

¹H-NMR (DMSO-d₆) δppm:

1.55-1.65 (2H, m), 1.65-1.8 (2H, m), 2.35-2.5 (4H, m), 2.55-2.7 (4H, m),2.78 (2H, t, J=7.5 Hz), 3.0-3.15 (4H, m), 3.93 (2H, t, J=6.4 Hz), 6.44(1H, d, J=2.5 Hz), 6.49 (1H, dd, J=2.5 Hz, 8.3 Hz), 6.89 (1H, d, J=7.5Hz), 7.04 (1H, d, J=8.3 Hz), 7.27 (1H, dd, J=7.8 Hz, 7.8 Hz), 7.35-7.45(1H, m), 7.61 (1H, d, J=8.1 Hz), 7.68 (1H, d, J=5.6 Hz), 9.97 (1H, bs).

Example 12 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-onehydrochloride

1N hydrochloric acid ethanol solution was added to an ethanol solutionof7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-oneprepared in Example 11, and precipitated crystals were filtrated andrecrystallized from 90% aqueous ethanol and7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-onehydrochloride was obtained as slightly brown needle-like crystals.

Melting point 237-239° C.

¹H-NMR (DMSO-d₆) δppm:

1.75-1.85 (2H, m), 1.85-2.0 (2H, m), 2.42 (2H, t, J=7.5 Hz), 2.79 (2H,t, J=7.5 Hz), 3.15-3.5 (6H, m), 3.5-3.7 (4H, m), 3.96 (2H, t, J=6 Hz),6.46 (1H, d, J=2.5 Hz), 6.5-6.55 (1H, m), 6.97 (1H, d, J=7.5 Hz), 7.07(1H, d, J=8.5 Hz), 7.32 (1H, dd, J=8 Hz, 8 Hz), 7.50 (1H, d, J=5.5 Hz),7.71 (1H, d, J=8 Hz), 7.77 (1H, d, J=5.5 Hz), 10.03 (1H, s), 10.65 (1H,br).

Example 13 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-(Z)-2-butenyloxy]-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Example 1,7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-(Z)-2-butenyloxy]-3,4-dihydro-1H-quinolin-2-onewas prepared from7-(4-chloro-(Z)-2-butenyloxy)-3,4-dihydro-1H-quinolin-2-one.

White powder (methanol)

Melting point 68-70° C.

¹H-NMR (DMSO-d₆) δppm:

2.42 (2H, t, J=7.5 Hz), 2.64 (4H, br), 2.79 (2H, t, J=7.5 Hz), 2.9-3.25(6H, m), 4.61 (2H, d, J=3 Hz), 5.65-5.9 (2H, m), 6.48 (1H, d, J=2.5 Hz),6.54 (1H, dd, J=2.5, 8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5Hz), 7.27 (1H, dd, J=8 Hz, 8 Hz), 7.40 (1H, d, J=5.5 Hz), 7.61 (1H, d,J=8 Hz), 7.69 (1H, d, J=5.5 Hz), 10.01 (1H, bs).

Example 14 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-3-methylbutoxy]-3,4-dihydro-1H-quinolin-2-onehydrochloride

By a similar method as in Example 1,7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-3-methylbutoxy]-3,4-dihydro-1H-quinolin-2-onewas prepared from methanesulfonic acid2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl ester, andafter it was made into a methanol solution, 0.5N hydrochloric acidmethanol solution was added thereto, precipitated crystals wereseparated by filtration, recrystallized from isopropyl alcohol andthereby7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-3-methylbutoxy]-3,4-dihydro-1H-quinolin-2-onehydrochloride was obtained in the form of a slightly yellow powder.

Melting point 217-219° C. (decomposed)

¹H-NMR (DMSO-d₆) δppm:

1.12 (3H, d, J=6.5 Hz), 1.55-1.7 (1H, m), 1.9-2.05 (1H, m), 2.2-2.3 (1H,m), 2.41 (2H, t, J=7.5 Hz), 2.79 (2H, t, J=7.5 Hz), 3.05-3.15 (1H, m),3.15-3.25 (1H, m), 3.25-3.45 (4H, m), 3.45-3.55 (2H, m), 3.55-3.7 (2H,m), 3.9-4.1 (2H, m), 6.49 (1H, d, J=2.5 Hz), 6.54 (1H, dd, J=2.5 Hz, 8.5Hz), 6.97 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.33 (1H, dd, J=8Hz, 8 Hz), 7.49 (1H, d, J=5.5 Hz), 7.70 (1H, d, J=8 Hz), 7.77 (1H, d,J=5.5 Hz), 10.03 (1H, bs), 10.66 (1H, br).

Example 15 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-(E)-2-butenyloxy]-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Example 1,7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-(E)-2-butenyloxy]-3,4-dihydro-1H-quinolin-2-onewas prepared from 7-(4-bromo-(E)-2-butenyloxy)-3,4-dihydro-1H-quinolin-2-one.

White powder (dichloromethane-diisopropyl ether)

Melting point 147.8-149.7° C.

¹H-NMR (CDCl₃) δ ppm:

2.61 (2H, t, J=7.5 Hz), 2.65-2.75 (4H, m), 2.90 (2H, t, J=7.5 Hz),3.1-3.2 (6H, m), 4.52 (2H, d, J=4.3 Hz), 5.9-6.0 (2H, m), 6.31 (1H, d,J=2.3 Hz), 6.55 (1H, dd, J=8.3 Hz, 2.3 Hz), 6.90 (1H, d, J=7.6 Hz), 7.05(1H, d, J=8.3 Hz), 7.27 (1H, m), 7.37-7.41 (2H, m), 7.53-7.60 (2H, m).

Example 16 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-4-methyl-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Example 1,7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-4-methyl-3,4-dihydro-1H-quinolin-2-onewas prepared from7-(4-chlorobutoxy)-4-methyl-3,4-dihydro-1H-quinolin-2-one.

White powder (methanol)

Melting point 112-115° C.

¹H-NMR (DMSO-ds) δppm:

1.14 (3H, d, J=7 Hz), 1.55-1.7 (2H, m), 1.7-1.8 (2H, m), 2.19 (1H, dd,J=7, 16 Hz), 2.43 (2H, t, J=7 Hz), 2.5-2.7 (5H, m), 2.9-3.0 (1H, m),3.0-3.1 (4H, m), 3.94 (2H, t, J=6.5 Hz), 6.45 (1H, d, J=2.5 Hz), 6.53(1H, dd, J=2.5, 8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.07 (1H, d, J=8.5 Hz),7.27 (1H, dd, J=8 Hz, 8 Hz), 7.39 (1H, d, J=5.5 Hz), 7.61 (1H, d, J=8Hz), 7.69 (1H, d, J=5.5 Hz), 9.98 (1H, bs).

Example 17 Preparation of7-{2-[2-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)ethoxy]ethoxy}-3,4-dihydro-1H-quinolin-2-onedihydrochloride

By a similar method as in Example 1,7-{2-[2-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)ethoxy]ethoxy}-3,4-dihydro-1H-quinolin-2-onewas prepared from7-[2-(2-chloroethoxy)ethoxy]-3,4-dihydro-1H-quinolin-2-one, and after itwas made into an ethanol solution, 1N hydrochloric acid ethanol solutionwas added thereto, precipitated crystals were separated by filtration,recrystallized from isopropyl alcohol-diisopropyl ether and thereby7-{2-[2-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)ethoxy]ethoxy}-3,4-dihydro-1H-quinolin-2-onedihydrochloride was obtained in the form of a white powder.

Melting point 172.3-177.2° C.

¹H-NMR (CDCl₃) δ ppm:

2.53 (2H, t, J=7.5 Hz), 2.80 (2H, t, J=7.5 Hz), 3.40 (2H, m), 3.54-3.59(2H, m), 3.79-3.94 (6H, m), 4.16-4.30 (6H, m), 6.50-6.53 (2H, m), 7.01(1H, d, J=8.0 Hz), 7.36 (1H, dd, J=8 Hz, 8 Hz), 7.53-7.62 (2H, m), 7.82(1H, d, J=8.0 Hz), 7.91 (1H, m), 8.02 (1H, brs), 13.31 (1H, brs).

Example 18 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1-methyl-3,4-dihydro-1H-quinolin-2-onehydrochloride

48 mg of sodium hydride (60% oily) was added to a solution of 0.40 g of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-onein dimethylformamide (5 ml) and tetrahydrofuran (5 ml) while beingstirred under ice-cooling and stirred at room temperature for 1 hour,and after that 0.07 ml of methyl iodide was added and stirred at roomtemperature for 1 hour. Water was added to the reaction solution, whichwas then extracted with ethyl acetate and, after washed with water,dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (dichloromethane:methanol=30:1). The solvent wasevaporated under reduced pressure and 0.5N hydrochloric acid ethanolsolution was added thereto, precipitated crystals were separated byfiltration, and thereby 0.15 g of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1-methyl-3,4-dihydro-1H-quinolin-2-onehydrochloride was obtained in the form of a slightly yellow powder.

Melting point 275.6-277.6° C.

¹H-NMR (DMSO-d₆) δppm:

1.70-1.94 (4H, m), 2.48-2.52 (2H, m), 2.77 (2H, t, J=7.2 Hz), 3.15-3.30(9H, m), 3.52-3.63 (4H, m), 4.03 (2H, t, J=6.0 Hz), 6.58-6.63 (2H, m),6.96 (1H, d, J=7.5 Hz), 7.11 (1H, d, J=8.1 Hz), 7.31 (1H, dd, J=7.8 Hz,7.8 Hz), 7.48 (1H, d, J=5.5 Hz), 7.69 (1H, d, J=8.0 Hz), 7.75 (1H, d,J=5.5 Hz), 10.61 (1H, br).

Example 19 Preparation of6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-onehydrochloride

By a similar method as in Example 1,6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-onewas prepared from 6-(3-chloropropoxy)-3,4-dihydro-1H-quinolin-2-one, andafter it was made into a methanol solution, 0.5N hydrochloric acidmethanol solution was added thereto, precipitated crystals wereseparated by filtration, recrystallized from a mixed solvent of ethylacetate-diethyl ether and thereby6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-onehydrochloride was obtained in the form of a white powder.

Melting point 231-234° C.

¹H-NMR (DMSO-d₆) δppm:

2.20-2.30 (2H, m), 2.35-2.45 (2H, m), 2.83 (2H, t, J=7.5 Hz), 3.20-3.70(10H, m), 4.02 (2H, t, J=5.9 Hz), 6.70-6.85 (3H, m), 6.96 (1H, d, J=7.6Hz), 7.31 (1H, dd, J=7.9 Hz, 7.9 Hz), 7.48 (1H, d, J=5.6 Hz), 7.69 (1H,d, J=8.1 Hz), 7.76 (1H, d, J=5.5 Hz), 9.93 (1H, brs), 10.90 (1H, brs).

Example 20 Preparation of6-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one

By a similar method as in Example 1,6-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-onewas prepared from 6-(4-bromobutoxy)-3,4-dihydro-1H-quinolin-2-one.

White powder (ethyl acetate-diethyl ether) Melting point 175-178° C.

¹H-NMR (CDCl₃) δppm:

1.65-1.90 (4H, m), 2.52 (2H, t, J=7.3 Hz), 2.55-2.65 (2H, m), 2.65-2.75(4H, m), 2.94 (2H, t, J=7.5 Hz), 3.15-3.25 (4H, m), 3.90-4.00 (2H, m),6.65-6.75 (3H, m), 6.89 (1H, dd, J=0.7 Hz, 7.6 Hz), 7.27 (1H, dd, J=7.9Hz, 7.9 Hz), 7.35-7.45 (2H, m), 7.55 (1H, d, J=8.0 Hz), 8.02 (1H, brs).

Example 21 Preparation of1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-3,4-dihydro-1H-quinolin-2-onehydrochloride

By a similar method as in Example 1,1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-3,4-dihydro-1H-quinolin-2-onewas prepared from 1-(4-chlorobutyl)-3,4-dihydro-1H-quinolin-2-one, andafter it was made into an ethanol solution, 1N hydrochloric acid ethanolsolution was added thereto, precipitated crystals were separated byfiltration and thereby1-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-3,4-dihydro-1H-quinolin-2-onehydrochloride was obtained in the form of a white powder.

Melting point 257.0-259.0° C.

¹H-NMR (DMSO-d₆) δppm:

1.60-1.80 (4H, m), 2.54 (2H, t, J=8.3 Hz), 2.87 (2H, t, J=7.9 Hz),3.10-3.30 (6H, m), 3.50-3.60 (4H, m), 3.95 (2H, t, J=7.0 Hz), 6.94-7.04(2H, m), 7.14-7.35 (4H, m), 7.48 (1H, d, J=5.6 Hz), 7.70 (1H, d, J=8.0Hz), 7.76 (1H, d, J=5.6 Hz), 10.00-10.20 (1H, m).

Example 22 Preparation of1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)pentyl]-3,4-dihydro-1H-quinolin-2-onehydrochloride

By a similar method as in Example 1,1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)pentyl]-3,4-dihydro-1H-quinolin-2-onewas prepared from 1-(5-chloropentyl)-3,4-dihydro-1H-quinolin-2-one, andafter it was made into an ethanol solution, 1N hydrochloric acid ethanolsolution was added thereto, precipitated crystals were separated byfiltration and thereby1-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)pentyl]-3,4-dihydro-1H-quinolin-2-onehydrochloride was obtained.

Melting point 242.0-244.0° C.

¹H-NMR (DMSO-d₆) δppm:

1.30-1.45 (2H, m), 1.50-1.65 (2H, m), 1.70-1.85 (2H, m), 2.53 (2H, t,J=8.2 Hz), 2.85 (2H, t, J=8.0 Hz), 3.10-3.30 (6H, m), 3.50-3.60 (4H, m),3.91 (2H, t, J=7.3 Hz), 6.94-7.03 (2H, m), 7.13-7.34 (4H, m), 7.47 (1H,d, J=5.6 Hz), 7.69 (1H, d, J=8.0 Hz), 7.76 (1H, d, J=5.5 Hz),10.30-10.50 (1H, m).

Example 23 Preparation of2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-3,4-dihydro-2H-isoquinolin-1-one hydrochloride

By a similar method as in Example 1,2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-3,4-dihydro-2H-isoquinolin-1-onewas prepared from 2-(4-chlorobutyl)-3,4-dihydro-2H-isoquinolin-1-one,and after it was made into an ethanol solution, 1N hydrochloric acidethanol solution was added thereto, precipitated crystals were separatedby filtration, recrystallized from a mixed solvent of isopropylalcohol-ethanol and thereby2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-3,4-dihydro-2H-isoquinolin-1-one hydrochloride was obtained.

Melting point 257.5-265.5° C.

¹H-NMR (DMSO-d₆) δppm:

1.6-1.9 (4H, m), 2.98-3.60 (16H, m), 6.98 (1H, d, J=7.7 Hz), 7.30-7.38(3H, m), 7.46-7.51 (2H, m), 7.71 (1H, d, J=8.2 Hz), 7.77 (1H, d, J=5.5Hz), 7.89 (1H, d, J=7.7 Hz), 10.10 (1H, brs).

Example 24 Preparation of2-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)pentyl]-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Example 1,2-[5-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)pentyl]-3,4-dihydro-2H-isoquinolin-1-onewas prepared from 2-(5-chloropentyl)-3,4-dihydro-2H-isoquinolin-1-one.

White powder (ethyl acetate-diisopropyl ether)

Melting point 91.8-93.3° C.

¹H-NMR (CDCl₃) δppm:

1.32-1.37 (2H, m), 1.56-1.64 (4H, m), 2.38 (2H, t, J=7.6 Hz), 2.62 (4H,m), 2.92 (2H, t, J=6.5 Hz), 3.09-3.11 (4H, m), 3.47-3.55 (4H, m), 6.81(1H, d, J=7.5 Hz), 7.08-7.11 (2H, m), 7.17-7.35 (4H, m), 7.47 (1H, d,J=8.0 Hz), 8.01 (1H, dd, J=7.5 Hz, 1.4 Hz).

Example 25 Preparation of6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Example 1,6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-onewas prepared from 6-(3-chloropropoxy)-3, 4-dihydro-2H-isoquinolin-1-one.

White powder (ethyl acetate-diethyl ether) Melting point 203-205° C.

¹H-NMR (CDC₃) δppm:

2.00-2.10 (2H, m), 2.60-2.70 (2H, m), 2.74 (4H, brs), 2.96 (2H, t, J=6.5Hz), 3.20 (4H, brs), 3.50-3.60 (2H, m), 4.11 (2H, t, J=6.3 Hz), 6.09(1H, brs), 6.73 (1H, s), 6.85-6.95 (2H, m), 7.25-7.30 (1H, m), 7.35-7.45(2H, m), 7.55 (1H, d, J=8.1 Hz), 8.01 (1H, d, J=8.6 Hz).

Example 26 Preparation of6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Example 18,6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onewas prepared from6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-oneusing methyl iodide.

White powder (ethyl acetate-diethyl ether)

Melting point 110-113° C.

¹H-NMR (CDCl₃) δppm:

2.05 (2H, t, J=6.9 Hz), 2.65 (2H, t, J=7.3 Hz), 2.74 (4H, brs), 2.97(2H, t, J=6.7 Hz), 3.14 (3H, s), 3.21 (4H, brs), 3.54 (2H, t, J=6.7 Hz),4.11 (2H, t, J=6.4 Hz), 6.68 (1H, s), 6.86 (1H, dd, J=2.3 Hz, 8.6 Hz),6.91 (1H, d, J=7.7 Hz), 7.25-7.30 (1H, m), 7.40 (1H, d, J=5.5 Hz), 7.42(1H, d, J=5.5 Hz), 7.56 (1H, d, J=7.9 Hz), 8.03 (1H, d, J=8.6 Hz).

Example 27 Preparation of6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Example 18,6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinolin-1-onewas prepared from6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-oneusing ethyl iodide.

White powder (ethyl acetate-diethyl ether)

Melting point 128-131° C.

¹H-NMR (CDCl₃) δppm:

1.21 (3H, t, J=7.2 Hz), 2.05 (2H, t, J=6.9 Hz), 2.65 (2H, t, J=7.3 Hz),2.74 (4H, brs), 2.96 (2H, t, J=6.6 Hz), 3.21 (4H, brs), 3.54 (2H, t,J=6.7 Hz), 3.62 (2H, q, J=7.2 Hz), 4.11 (2H, t, J=6.3 Hz), 6.68 (1H, d,J=1.7 Hz), 6.86 (1H, dd, J=2.3 Hz, 8.2 Hz), 6.91 (1H, d, J=7.7 Hz),7.25-7.30 (1H, m), 7.40 (1H, d, J=5.5 Hz), 7.42 (1H, d, J=5.5 Hz), 7.56(1H, d, J=7.8 Hz), 8.03 (1H, d, J=8.6 Hz).

Example 28 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Example 1,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-onewas prepared from 7-(3-chloropropoxy)-3, 4-dihydro-2H-isoquinolin-1-one.

White powder (ethyl acetate-diethyl ether)

Melting point 176-179° C.

¹H-NMR (CDCl₃) δppm:

2.00-2.10 (2H, m), 2.64 (2H, t, J=7.3 Hz), 2.73 (4H, brs), 2.94 (2H, t,J=6.6 Hz), 3.20 (4H, brs), 3.50-3.60 (2H, m), 4.12 (2H, t, J=6.3 Hz),5.92 (1H, brs), 6.90 (1H, d, J=7.7 Hz), 7.03 (1H, dd, J=2.8 Hz, 8.3 Hz),7.13 (1H, d, J=8.3 Hz), 7.25-7.30 (1H, m), 7.39 (1H, d, J=5.5 Hz), 7.42(1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.1 Hz), 7.62 (1H, d, J=2.7 Hz).

Example 29 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Example 18,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onewas prepared from7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-oneusing methyl iodide.

White powder (ethanol)

Melting point 115-117° C.

¹H-NMR (CDCl₃) δppm:

1.95-2.10 (2H, m), 2.64 (2H, t, J=7.3 Hz), 2.70-2.80 (4H, m), 2.94 (2H,t, J=6.7 Hz), 3.10-3.25 (4H, m), 3.16 (3H, s), 2.54 (2H, t, J=6.7 Hz),4.11 (2H, t, J=6.5 Hz), 6.90 (1H, d, J=7.0 Hz), 6.98 (1H, dd, J=2.7 Hz,8.3 Hz), 7.08 (1H, d, J=8.3 Hz), 7.28 (1H, dd, J=7.9 Hz, 7.9 Hz),7.35-7.45 (2H, m), 7.55 (1H, d, J=8.1 Hz), 7.63 (1H, d, J=2.6 Hz).

Example 30 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onehydrochloride

After7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onewas made into an ethanol solution, 1N hydrochloric acid ethanol solutionwas added thereto, precipitated crystals were separated by filtration,recrystallized from ethanol and thereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onehydrochloride was obtained in the form of a white powder.

Melting point 229-233° C.

¹H-NMR (DMSO-d₆) δppm:

2.20-2.30 (2H, m), 2.89 (2H, t, J=6.7 Hz), 3.01 (3H, s), 3.21 (2H, t,J=6.9 Hz), 3.30-3.60 (8H, m), 3.60-3.70 (2H, m), 4.11 (2H, t, J=6.0 Hz),6.97 (1H, d, J=7.7 Hz), 7.06 (1H, dd, J=2.8 Hz, 8.3 Hz), 7.22 (1H, d,J=7.9 Hz), 7.31 (1H, dd, J=7.8 Hz, 7.8 Hz), 7.41 (1H, d, J=2.7 Hz), 7.49(1H, d, J=5.5 Hz), 7.69 (1H, d, J=8.1 Hz), 7.76 (1H, d, J=5.5 Hz), 10.70(1H, brs).

Example 31 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinolin-1-onedihydrochloride

By a similar method as in Example 18,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinolin-1-onewas prepared from7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-oneusing ethyl iodide, and after it was made into a methanol solution, 0.5Nhydrochloric acid methanol solution was added thereto, precipitatedcrystals were separated by filtration, recrystallized from a mixedsolvent of methanol-ethyl acetate and thereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinolin-1-onedihydrochloride was obtained in the form of a white powder.

Melting point 210-213° C.

¹H-NMR (DMSO-d₆) δppm:

1.09 (3H, t, J=7.1 Hz), 2.20-2.30 (2H, m), 2.87 (2H, t, J=6.5 Hz),3.20-3.70 (14H, m), 4.11 (2H, t, J=5.9 Hz), 6.96 (1H, d, J=7.7 Hz),7.00-7.10 (1H, m), 7.22 (1H, d, J=8.3 Hz), 7.25-7.35 (1H, m), 7.41 (1H,d, J=2.7 Hz), 7.48 (1H, d, J=5.5 Hz), 7.69 (1H, d, J=7.7 Hz), 7.76 (11H,d, J=5.5 Hz), 11.08 (1H, brs).

Example 32 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onehydrochloride

By a similar method as in Example 1,7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onewas prepared from 7-(4-chlorobutoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one, and after it was made into a methanolsolution, 0.5N hydrochloric acid methanol solution was added thereto,precipitated crystals were separated by filtration, recrystallized froma mixed solvent of methanol-ethyl acetate and thereby7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onehydrochloride was obtained in the form of a white powder.

Melting point 213-218° C.

¹H-NMR (DMSO-d₆) δppm:

1.70-2.00 (4H, m), 2.88 (2H, t, J=6.6 Hz), 3.01 (3H, s), 3.10-3.70 (12H,m), 4.03 (2H, t, J=5.8 Hz), 6.95 (1H, d, J=7.5 Hz), 7.04 (1H, dd, J=2.8Hz, 8.5 Hz), 7.20 (1H, d, J=8.4 Hz), 7.31 (1H, dd, J=7.8 Hz, 7.8 Hz),7.39 (1H, d, J=2.7 Hz), 7.48 (1H, d, J=5.7 Hz), 7.69 (1H, d, J=8.1 Hz),7.75 (1H, d, J=5.5 Hz), 10.71 (1H, brs).

Example 33 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-2H-isoquinolin-1-onehydrochloride

By a similar method as in Example 1,7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-2H-isoquinolin-1-onewas prepared from 7-(4-chlorobutoxy)-3,4-dihydro-2H-isoquinolin-1-one,and after it was made into an ethyl acetate solution, 1N hydrochloricacid ethanol solution was added thereto, precipitated crystals wereseparated by filtration, recrystallized from ethyl acetate and thereby7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-2H-isoquinolin-1-onehydrochloride was obtained in the form of a white powder.

Melting point 223.8-226.8° C.

¹H-NMR (DMSO-d₆) δppm:

1.81-1.93 (4H, m), 2.83 (2H, t, J=6.5 Hz), 3.16-3.32 (8H, m), 3.43-3.64(4H, m), 4.06 (2H, t, J=5.9 Hz), 6.97 (1H, d, J=7.6 Hz), 7.07 (1H, dd,J=8.3 Hz, 2.7 Hz), 7.24 (1H, d, J=7.7 Hz), 7.32 (1H, dd, J=7.9 Hz, 7.9Hz), 7.39 (1H, d, J=2.7 Hz), 7.50 (1H, d, J=5.6 Hz), 7.71 (1H, d, J=8.0Hz), 7.77 (1H, d, J=5.5 Hz), 7.95 (1H, s), 10.62 (1H, s).

Example 34 Preparation of2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-2H-isoquinolin-1-one

By a similar method as in Example 1,2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-2H-isoquinolin-1-onewas prepared from 2-(4-chlorobutyl)-2H-isoquinolin-1-one.

Pale brown powder (ethyl acetate-diisopropyl ether)

Melting point 141.1-142.7° C.

¹H-NMR (CDCl₃) δppm:

1.62 (2H, m), 1.87 (2H, m), 2.50 (2H, t, J=7.4 Hz), 2.66-2.71 (4H, m),3.16-3.19 (4H, m), 4.06 (2H, t, J=7.2 Hz), 6.50 (1H, d, J=7.3 Hz), 6.89(1H, d, J=7.7 Hz), 7.08 (1H, d, J=7.3 Hz), 7.24-7.65 (7H, m), 8.44 (1H,d, J=7.9 Hz).

Example 35 Preparation of 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2H-isoquinolin-1-one

By a similar method as in Example 1,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2H-isoquinolin-1-onewas prepared from 7-(3-chloropropoxy)-2H-isoquinolin-1-one.

White powder (ethyl acetate)

Melting point 220.1-222.5° C.

¹H-MMR (DMSO-d₆) δppm:

1.99 (2H, quint, J=6.6 Hz), 2.57 (2H, t, J=7.0 Hz), 2.66 (4H, brs), 3.09(4H, brs), 4.16 (2H, t, J=6.3 Hz), 6.52 (1H, d, J=7.1 Hz), 6.90 (1H, d,J=7.4 Hz), 7.04 (1H, dd, J=6.9 Hz, 6.9 Hz), 7.26 (1H, d, J=7.9 Hz), 7.33(1H, dd, J=8.8 Hz, 2.8 Hz), 7.41 (1H, d, J=5.5 Hz), 7.59-7.63 (3H, m),7.69 (1H, d, J=5.5 Hz), 11.21 (1H, d, J=4.9 Hz).

Example 36 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-2H-isoquinolin-1-onehydrochloride

By a similar method as in Example 18,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-2H-isoquinolin-1-onewas prepared from7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2H-isoquinolin-1-oneusing methyl iodide, and after it was made into an ethyl acetatesolution, 1N hydrochloric acid ethanol solution was added thereto,precipitated crystals were separated by filtration, recrystallized fromethyl acetate and thereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-2H-isoquinolin-1-onehydrochloride was obtained in the form of a white powder.

Melting point 227.6-230.2° C.

¹H-NMR (DMSO-d₆) δppm:

2.31 (2H, quint, J=7.0 Hz), 3.20-3.40 (6H, m), 3.52 (3H, s), 3.54-3.70(4H, m), 4.23 (2H, t, J=5.8 Hz), 6.60 (1H, d, J=7.3 Hz), 6.99 (1H, d,J=7.7 Hz), 7.30-7.38 (3H, m), 7.51 (1H, d, J=5.6 Hz), 7.63-7.73 (3H, m),7.78 (1H, d, J=5.5 Hz), 10.88 (1H, s).

Example 37 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-ethyl-2H-isoquinolin-1-onehydrochloride

By a similar method as in Example 1,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-ethyl-2H-isoquinolin-1-onewas prepared from 7-(3-chloropropoxy)-2-ethyl-2H-isoquinolin-1-one, andafter it was made into an ethyl acetate solution, 1N hydrochloric acidethanol solution was added thereto, precipitated crystals were separatedby filtration, recrystallized from ethyl acetate and thereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-ethyl-2H-isoquinolin-1-onehydrochloride was obtained in the form of a white powder.

Melting point 229.9-231.2° C.

¹H-NMR (DMSO-d₆) δppm:

1.25 (3H, t, J=7.1 Hz), 2.29 (2H, brs), 3.14-3.49 (6H, m), 3.56-3.72(4H, m), 4.00 (2H, q, J=7.2 Hz), 4.23 (2H, t, J=5.9 Hz), 6.62 (1H, d,J=7.3 Hz), 6.99 (1H, d, J=7.6 Hz), 7.27-7.39 (3H, m), 7.51 (1H, d, J=5.6Hz), 7.62-7.73 (3H, m), 7.78 (1H, d, J=5.5 Hz), 10.38 (1H, s).

Example 38 Preparation of2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-7-methoxy-2H-isoquinolin-1-onehydrochloride

By a similar method as in Example 1,2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-7-methoxy-2H-isoquinolin-1-onewas prepared from 2-(4-chlorobutyl)-7-methoxy-2H-isoquinolin-1-one, andafter it was made into an ethyl acetate solution, 1N hydrochloric acidethanol solution was added thereto, precipitated crystals were separatedby filtration, recrystallized from ethyl acetate and thereby2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-7-methoxy-2H-isoquinolin-1-onehydrochloride was obtained in the form of a white powder.

Melting point 243.5-245.6° C.

¹H-NMR (DMSO-d₆) δppm:

1.78 (4H, brs), 3.10-3.28 (6H, m), 3.56 (4H, t, J=9.6 Hz), 3.87 (3H, s),4.04 (2H, t, J=5.3 Hz), 6.64 (1H, d, J=7.3 Hz), 6.96 (1H, d, J=7.6 Hz),7.30 (1H, d, J=8.0 Hz), 7.34 (1H, dd, J=8.6 Hz, 2.9 Hz), 7.41 (1H, d,J=7.3 Hz), 7.49 (1H, d, J=5.6 Hz), 7.63 (1H, d, J=8.6 Hz), 7.69 (1H, dd,J=8.0 Hz, 8.0 Hz), 7.77 (1H, d, J=5.5 Hz), 10.60 (1H, s).

Example 39 Preparation of2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-7-hydroxy-2H-isoquinolin-1-onehydrobromide

Boron tribromide (2M dichloromethane solution, 1.0 ml) was added to adichloromethane (50 ml) solution of2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-7-methoxy-2H-isoquinolin-1-one(0.16 g) while being stirred under ice-cooling and stirred at roomtemperature for 3 days. Water was added to the reaction solution, whichwas then stirred at room temperature for 0.5 hour. Precipitated crystalswere separated by filtration, recrystallized from ethyl acetate andthereby2-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl]-7-hydroxy-2H-isoquinolin-1-onehydrobromide (0.13 g) was obtained in the form of a white powder.

Melting point 273.6-275.7° C.

¹H-NMR (DMSO-d₆) δppm:

1.75 (4H, brs), 3.08 (2H, t, J=11.1 Hz), 3.16-3.28 (4H, m), 3.59 (2H, t,J=10.5 Hz), 4.01 (2H, brs), 6.58 (1H, d, J=7.3 Hz), 6.97 (1H, d, J=7.5Hz), 7.19 (1H, dd, J=8.6 Hz, 2.6 Hz), 7.29-7.36 (2H, m), 7.49-7.65 (3H,m), 7.71 (1H, d, J=8.0 Hz), 7.78 (1H, d, J=5.5 Hz), 9.50 (1H, brs), 9.95(1H, s).

Example 40 Preparation of6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2H-isoquinolin-1-one

By a similar method as in Example 1,6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2H-isoquinolin-1-onewas prepared from 6-chloropropoxy-2H-isoquinolin-1-one.

White powder (ethyl acetate)

Melting point 228.8-230.7° C.

¹H-NMR (DMSO-d₆) δppm:

1.98 (2H, quint, J=6.7 Hz), 2.56 (2H, t, J=7.0 Hz), 2.65 (4H, brs), 3.09(4H, brs), 4.17 (2H, t, J=6.3 Hz), 6.47 (1H, d, J=7.1 Hz), 6.90 (1H, d,J=7.6 Hz), 7.05 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.10-7.15 (2H, m), 7.28 (1H,d, J=7.8 Hz), 7.41 (1H, d, J=5.5 Hz), 7.62 (1H, d, J=8.0 Hz), 7.70 (1H,d, J=5.5 Hz), 8.07 (1H, d, J=8.8 Hz), 11.03 (1H, s).

Example 41 Preparation of6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-2H-isoquinolin-1-onehydrochloride

By a similar method as in Example 18,6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-2H-isoquinolin-1-onewas prepared from6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2H-isoquinolin-1-oneusing methyl iodide, and after it was made into an ethyl acetatesolution, 1N hydrochloric acid ethanol solution was added thereto,precipitated crystals were separated by filtration, recrystallized fromethyl acetate and thereby6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-2H-isoquinolin-1-onehydrochloride was obtained in the form of a white powder.

Melting point 241.4-244.8° C.

¹H-NMR (DMSO-d₆) δppm:

2.31 (2H, t, J=7.6 Hz), 3.46 (3H, s), 3.19-3.70 (10H, m), 4.24 (2H, t,J=5.9 Hz), 6.54 (1H, d, J=7.4 Hz), 6.99 (1H, d, J=7.6 Hz), 7.10 (1H, dd,J=8.8 Hz, 2.4 Hz), 7.15 (1H, d, J=2.3 Hz), 7.33 (1H, dd, J=7.9 Hz, 7.9Hz), 7.45 (1H, d, J=7.1 Hz), 7.51 (1H, d, J=5.5 Hz), 7.71 (1H, d, J=8.0Hz), 7.78 (1H, d, J=5.5 Hz), 8.14 (1H, d, J=8.8 Hz), 10.86 (1H, s).

Example 42 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onehydrochloride

1N hydrochloric acid aqueous solution was added to a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onein methanol and dichloromethane and the solvent was evaporated underreduced pressure. The residue was recrystallized from 70% ethanol andthereby7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onehydrochloride was obtained in the form of a white powder.

Melting point 238-241° C.

¹H-NMR (DMSO-d₆) δppm:

1.80-2.00 (4H, m), 3.20-3.45 (6H, m), 3.50-3.60 (4H, m), 4.06 (2H, t,J=5.6 Hz), 6.28 (1H, d, J=9.5 Hz), 6.75-6.85 (2H, m), 6.95 (1H, d, J=7.5Hz), 7.30 (1H, dd, J=7.8 Hz, 7.8 Hz), 7.47 (1H, d, J=5.7 Hz), 7.56 (1H,d, J=8.4 Hz), 7.68 (1H, d, J=8.1 Hz), 7.70-7.85 (2H, m), 10.92 (1H,brs), 11.61 (1H, brs).

Example 43 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onesulfate

Dilute sulphuric acid was added to a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onein methanol and dichloromethane and the solvent was evaporated underreduced pressure. The residue was recrystallized from 60% ethanol andthereby7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onesulfate was obtained in the form of a white powder.

Melting point 248-251° C.

¹H-NMR (DMSO-d₆) δ ppm:

1.80-1.95 (4H, m), 2.50-4.00 (10H, m), 4.00-4.10 (2H, m), 6.30 (1H, d,J=8.2 Hz), 6.75-6.85 (2H, m), 6.97 (1H, d, J=7.6 Hz), 7.31 (1H, dd,J=7.8 Hz, 7.8 Hz), 7.49 (1H, d, J=5.6 Hz), 7.55-7.60 (1H, m), 7.70 (11H,d, J=8.0 Hz), 7.75-7.85 (2H, m), 9.25-9.75 (1H, br), 11.62 (1H, brs).

Example 44 Preparation of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one maleate

A methanol solution of maleic acid was added to a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onein methanol and dichloromethane and the solvent was evaporated underreduced pressure. The residue was recrystallized from 80% ethanol andthereby7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onemaleate was obtained in the form of a white powder.

Melting point 181.6-182.8° C.

¹H-NMR (DMSO-d₆) δppm:

1.87 (2H, brs), 3.26-3.47 (10H, m), 4.10 (2H, s), 6.07 (2H, s), 6.33(1H, d, J=9.5 Hz), 6.82-6.84 (2H, m), 6.99 (1H, d, J=7.6 Hz), 7.33 (1H,d, J=7.8 Hz), 7.51 (1H, d, J=5.5 Hz), 7.59 (1H, d, J=9.3 Hz), 7.70-7.85(3H, m), 11.65 (1H, s).

Example 45 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onefumarate

Fumaric acid was added to a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onein methanol and dichloromethane and the solvent was evaporated underreduced pressure. The residue was recrystallized from ethanol andthereby7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-H-quinolin-2-onefumarate was obtained in the form of a white powder.

Melting point 209-211° C.

¹H-NMR (DMSO-d₆) δppm:

1.60-1.90 (4H, m), 2.47-2.50 (2H, m), 2.60-2.75 (4H, m), 3.00-3.15 (4H,m), 4.05 (2H, t, J=6.3 Hz), 6.28 (1H, d, J=9.4 Hz), 6.60 (2H, s),6.76-6.82 (2H, m), 6.88 (1H, d, J=7.4 Hz), 7.26 (1H, dd, J=7.9 Hz, 7.8Hz), 7.39 (1H, d, J=5.9 Hz), 7.54 (1H, d, J=9.4 Hz), 7.61 (1H, d, J=8.0Hz), 7.69 (1H, d, J=5.5 Hz), 7.79 (1H, d, J=9.5 Hz), 11.58 (1H, brs).

Example 46 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onecitrate

Citric acid was added to a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onein methanol and dichloromethane and the solvent was evaporated underreduced pressure. The residue was recrystallized from 50% ethanol andthereby7-[4-(4-benzo[b]thiophen-4-yl-piperazin--yl)butoxy]-1H-quinolin-2-onecitrate was obtained in the form of a white powder.

Melting point 183-185° C.

¹H-NMR (DMSO-d₆) δppm:

1.50-2.00 (4H, m), 2.58 (2H, s), 2.62 (2H, s), 2.75-2.85 (2H, m),2.95-3.05 (4H, m), 3.10-3.20 (4H, m), 4.05 (2H, t, J=5.3 Hz), 6.28 (1H,d, J=9.4 Hz), 6.75-6.85 (2H, m), 6.90 (1H, d, J=7.6 Hz), 7.27 (1H, dd,J=7.9 Hz, 7.9 Hz), 7.42 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=9.3 Hz), 7.64(1H, d, J=8.0 Hz), 7.71 (1H, d, J=5.5 Hz), 7.79 (1H, d, J=9.5 Hz), 11.59(1H, brs).

Example 47 Preparation of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onep-toluenesulfonate

p-Toluenesulfonic acid monohydrate was added to a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onein methanol and dichloromethane and the solvent was evaporated underreduced pressure. The residue was recrystallized from methanol andthereby7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onep-toluenesulfonate was obtained in the form of a white powder.

Melting point 121.0-125.0° C.

¹H-NMR (DMSO-d₆) δppm:

1.73-2.00 (4H, m), 2.28 (3H, s), 3.07 (2H, J=11.0 Hz), 3.23-3.43 (4H,m), 3.62 (4H, t, J=15.0 Hz), 4.09 (2H, t, J=7.1 Hz), 6.31 (1H, dd, J=9.5Hz, 2.3 Hz), 6.80 (1H, s), 6.84 (1H, d, J=2.3 Hz), 6.98 (1H, d, J=7.5Hz), 7.11 (2H, d, J=8.0 Hz), 7.33 (1H, dd, J=7.5 Hz, 7.5 Hz), 7.46-7.52(3H, m), 7.58 (1H, d, J=9.5 Hz), 7.72 (1H, d, J=7.5 Hz), 7.78 (1H, d,J=11.3 Hz), 7.81 (1H, d, J=9.5 Hz), 9.31-9.49 (1H, m), 11.54-11.63 (1H,m).

Example 48 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onesulfate

Dilute sulphuric acid was added to a solution of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onein ethanol and dichloromethane and the solvent was evaporated underreduced pressure. The residue was recrystallized from 85% ethanol andthereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onesulfate was obtained in the form of a white powder.

Melting point 222-224° C.

¹H-NMR (DMSO-d₆) δppm:

2.10-2.30 (2H, m), 2.91 (2H, t, J=6.6 Hz), 3.03 (3H, s), 3.05-4.00 (12H,m), 4.13 (2H, t, J=5.9 Hz), 6.99 (1H, d, J=7.5 Hz), 7.09 (1H, dd, J=2.7Hz, 8.3 Hz), 7.24 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=7.8 Hz, 7.8 Hz),7.44 (1H, d, J=2.7 Hz), 7.51 (1H, d, J=5.5 Hz), 7.72 (1H, d, J=8.1 Hz),7.78 (1H, d, J=5.5 Hz), 9.00-10.05 (1H, br).

Example 49 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onefumarate

Fumaric acid was added to an ethanol solution of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-oneand the solvent was evaporated under reduced pressure. The residue wasrecrystallized from 70% ethanol and thereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onefumarate was obtained in the form of a pale yellow powder.

Melting point 149-151° C.

¹H-NMR (DMSO-d₆) δppm:

1.85-2.00 (2H, m), 2.58 (2H, t, J=7.2 Hz), 2.65-2.75 (4H, m), 2.88 (2H,t, J=6.7 Hz), 3.01 (3H, s), 3.05-3.15 (4H, m), 3.50 (2H, t, J=6.7 Hz),4.05 (2H, t, J=6.3 Hz), 6.60 (2H, s), 6.89 (1H, d, J=7.6 Hz), 7.03 (1H,dd, J=8.3 Hz, 2.7 Hz), 7.19 (1H, d, J=8.3 Hz), 7.27 (1H, dd, J=7.9 Hz,7.8 Hz), 7.38 (1H, d, J=3.0 Hz), 7.40 (1H, d, J=5.9 Hz), 7.61 (1H, d,J=8.0 Hz), 7.69 (1H, d, J=5.5 Hz).

Example 50 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onedifumarate

Fumaric acid was added to an ethanol solution of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-oneand the solvent was evaporated under reduced pressure. The residue wasrecrystallized from 90% ethanol and thereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onedifumarate was obtained in the form of white prism crystal.

Melting point 188-189° C.

¹H-NMR (DMSO-d₆) δ ppm:

1.85-2.00 (2H, m), 2.60 (2H, t, J=7.0 Hz), 2.65-2.75 (4H, m), 2.88 (2H,t, J=6.6 Hz), 3.01 (3H, s), 3.00-3.10 (4H, m), 3.50 (2H, t, J=6.7 Hz),4.05 (2H, t, J=6.4 Hz), 6.61 (4H, s), 6.90 (1H, d, J=7.5 Hz), 7.04 (1H,dd, J=8.2 Hz, 2.8 Hz), 7.19 (1H, d, J=8.4 Hz), 7.27 (1H, dd, J=7.9 Hz,7.8 Hz), 7.38 (1H, d, J=3.0 Hz), 7.40 (1H, d, J=6.2 Hz), 7.61 (1H, d,J=8.0 Hz), 7.69 (1H, d, J=5.5 Hz).

Example 51 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onemaleate

A methanol solution of maleic acid was added to a solution of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onein methanol and dichloromethane and the solvent was evaporated underreduced pressure. The residue was recrystallized from ethanol and ethylacetate and thereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onemaleate was obtained in the form of a white powder.

Melting point 134.6-135.5° C.

¹H-NMR (DMSO-d₆) δppm:

2.17 (2H, brs), 2.91 (2H, t, J=6.7 Hz), 3.03 (3H, s), 3.33 (10H, brs),3.52 (2H, t, J=6.7 Hz), 4.12 (2H, t, J=5.9 Hz), 6.04 (2H, s), 6.99 (1H,d, J=7.6 Hz), 7.07 (1H, dd, J=8.3 Hz, 2.6 Hz), 7.24 (1H, d, J=8.4 Hz),7.32 (1H, dd, J=7.9 Hz, 7.9 Hz), 7.43 (1H, d, J=2.6 Hz), 7.50 (1H, d,J=5.5 Hz), 7.71 (1H, d, J=7.9 Hz), 7.77 (1H, d, J=5.5 Hz).

Example 52 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onep-toluenesulfonate

p-Toluenesulfonic acid monohydrate was added to a solution of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onein methanol and dichloromethane and the solvent was evaporated underreduced pressure. The residue was recrystallized from ethanol and ethylacetate and thereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onep-toluenesulfonate was obtained in the form of a white powder.

Melting point 173.0-175.5° C.

¹H-NMR (DMSO-d₆) δppm:

2.00-2.33 (2H, m), 2.28 (3H, s), 2.91 (2H, t, J=6.6 Hz), 3.02 (3H, s),3.00-3.16 (2H, m), 3.29-3.80 (10H, m), 4.12 (2H, t, J=5.5 Hz), 6.99 (1H,d, J=7.9 Hz), 7.06 (1H, d, J=2.5 Hz), 7.11 (2H, d, J=7.9 Hz), 7.24 (1H,d, J=8.0 Hz), 7.33 (1H, dd, J=8.0 Hz, 8.0 Hz), 7.44 (1H, d, J=2.5 Hz),7.48 (18, d, J=7.9 Hz), 7.51 (1H, d, J=5.5 Hz), 7.72 (1H, d, J=8.0 Hz),7.82 (1H, d, J=5.5 Hz), 9.39-9.58 (1H, m)

Example 53 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one

By a similar method as in Example 1,7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onewas prepared from7-(3-chloropropoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one.

White powder (ethanol)

Melting point 115-117° C.

¹H-NMR (CDCl₃) δ ppm:

1.95-2.10 (2H, m), 2.64 (2H, t, J=7.3 Hz), 2.70-2.80 (4H, m), 2.94 (2H,t, J=6.7 Hz), 3.10-3.25 (4H, m), 3.16 (3H, s), 2.54 (2H, t, J=6.7 Hz),4.11 (2H, t, J=6.5 Hz), 6.90 (1H, d, J=7.0 Hz), 6.98 (1H, dd, J=2.7 Hz,8.3 Hz), 7.08 (1H, d, J=8.3 Hz), 7.28 (1H, dd, J=7.9 Hz, 7.9 Hz),7.35-7.45 (2H, m), 7.55 (1H, d, J=8.1 Hz), 7.63 (1H, d, J=2.6 Hz).

Example 54 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onemethanesulfonate

Methanesulfonic acid was added to an ethanol solution of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-oneand the solvent was evaporated under reduced pressure. The residue wasrecrystallized from 80% ethanol and thereby7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-onemethanesulfonate was obtained in the form of pale yellow prism crystal.

Melting point 147-149° C.

¹H-NMR (DMSO-d₆) δppm:

2.10-2.25 (2H, m), 2.29 (3H, s), 2.90 (2H, t, J=6.7 Hz), 3.02 (3H, s),3.05-3.15 (2H, m), 3.40-3.50 (4H, m), 3.51 (2H, t, J=6.7 Hz), 3.55-3.70(4H, m), 4.12 (2H, t, J=6.0 Hz), 6.98 (1H, d, J=7.6 Hz), 7.06 (1H, dd,J=8.3 Hz, 2.7 Hz), 7.23 (1H, d, J=8.4 Hz), 7.32 (1H, dd, J=7.9 Hz, 7.8Hz), 7.43 (1H, d, J=2.7 Hz), 7.50 (1H, d, J=5.5 Hz), 7.71 (1H, d, J=8.1Hz), 7.77 (1H, d, J=5.5 Hz), 9.40-9.60 (1H, m).

Example 55 Preparation of4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolinehydrochloride

4-Chloroquinoline (230 mg, 1.58 mmol),3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol (310 mg, 1.05mmol), and potassium carbonate (220 mg, 1.6 mmol) were added todimethylformamide (10 ml), followed by stirring at 80° C. for 5 hours.The reaction mixture was cooled to room temperature, then water wasadded thereto and the reaction mixture was extracted with ethyl acetate.The organic phase was washed with water, dried over magnesium sulfate,and concentrated under reduced pressure after filtration. The residuewas purified by basic silica gel column chromatography (n-hexane: ethylacetate=4:1), and concentrated under reduced pressure. The resultingresidue was dissolved in ethanol (3 ml), and 1N-HCl-ethanol solution (1ml) was added thereto. Insoluble matters produced were filtered out anddried to obtain4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolinehydrochloride (360 mg, yield: 78%) as light yellow powder.

Melting point: 240-242° C.

Example 56 Preparation of3-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]isoquinolinehydrochloride

3-Hydroxyisoquinoline (170 mg, 1.17 mmol),1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine (290 mg, 1.0 mmol),and potassium carbonate (200 mg, 1.45 mmol) were added todimethylformamide (8 ml), followed by stirring at 80° C. for 7 hours.The reaction mixture was cooled to room temperature, then water wasadded thereto and the reaction mixture was extracted with ethyl acetate.The organic phase was washed with water, dried over magnesium sulfate,and concentrated under reduced pressure after filtration. The residuewas purified by basic silica gel column chromatography (n-hexane: ethylacetate=9:1), and concentrated under reduced pressure. The resultingresidue was dissolved in ethanol (2 ml), and 1N-HCl-ethanol solution(0.5 ml) was added thereto. Insoluble matters produced were filtered outand dried to obtain3-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]isoquinolinehydrochloride (160 mg, yield: 37%) as white powder.

Melting point: 227-229° C.

Example 57 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-6-methoxy-3,4-dihydroisoquinolinedihydrochloride

PS-triphenylphosphine (110 mg, 3 mmol/g) and dibenzyl azodicarboxylate(70 mg, 0.3 mmol) were added to a solution of7-hydroxy-6-methoxy-3,4-dihydroisoquinoline (80 mg, 0.45 mmol) and3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol (83 mg, 0.3 mmol)in tetrahydrofuran (1 ml), followed by stirring at 50° C. for 3 hours.The reaction mixture was cooled to room temperature and insolublematters were removed by filtration. The filtrate was concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (n-hexane:ethyl acetate=1:1), and concentrated underreduced pressure. The resulting residue was dissolved in 2-propanol, and1N-HCl-ethanol solution was added thereto. Isopropyl ether was furtheradded thereto, then crystals precipitated were filtered out and dried toobtain7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-6-methoxy-3,4-dihydroisoquinolinedihydrochloride (26 mg, yield: 17%) as light yellow powder.

Melting point: 211.0-213.0° C.

Example 58 Preparation of1-acetyl-7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1,2,3,4-tetrahydroquinolinehydrochloride

Acetic anhydride (0.34 ml, 3.6 mmol) and pyridine (0.34 ml, 4.3 mmol)were added to a solution of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1,2,3,4-tetrahydroquinoline(0.49 g, 1.2 mmol) in methylene chloride (10 ml) with cooling in anice-bath, followed by stirring at room temperature overnight. Thereaction mixture was concentrated under reduced pressure, and water andethyl acetate were added to the residue to separate the organic phasefrom the water phase. The organic phase was washed with water, saturatedsodium hydrogencarbonate aqueous solution and brine in this order, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (n-hexane:ethyl acetate=1:1), andconcentrated under reduced pressure. The resulting residue was dissolvedin ethyl acetate (10 ml), and 1N—HCl-ethanol solution was added thereto.Then, crystals precipitated were filtered out and dried to obtain1-acetyl-7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1,2,3,4-tetrahydroquinolinehydrochloride (0.27 g, yield: 52%) as white powder.

Melting point: 123.2-124.3° C.

Example 59 Preparation of6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1,2,3,4-tetrahydroquinolinehydrochloride

Lithium aluminum hydride (160 mg, 4.2 mmol) was added to a solution of6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one(1.6 g, 3.8 mmol) in tetrahydrofuran (40 ml), followed by stirring underreflux for 1 hour. The reaction mixture was cooled in an ice-bath, andwater (0.16 ml), 15% sodium hydroxide aqueous solution (0.16 ml) andwater (0.5 ml) were added thereto in this order. After stirring themixture, insoluble matters were removed by filtration and the filtratewas concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (n-hexane:ethyl acetate=1:1), andconcentrated under reduced pressure to obtain amorphous solid (1.4 g).The amorphous solid obtained (0.6 g) was dissolved in ethyl acetate (15ml). 1N—HCl-ethanol solution (1.45 ml) was further added thereto, thencrystals precipitated were filtered out and dried to obtain6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1,2,3,4-tetrahydroquinolinehydrochloride (0.55 g) as white powder.

Melting point: 123.2-124.3° C.

Example 60 Preparation of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-1,2,3,4-tetrahydroquinolinehydrochloride

37% Formaldehyde aqueous solution (0.15 ml, 1.8 mmol),MP-cyanoborohydride (2.41 mmol/g, 0.76 g, 1.8 mmol) and catalytic amountof acetic acid were added to a solution of7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1,2,3,4-tetrahydroisoquinoline(0.25 g, 0.6 mmol) in methanol (20 ml), followed by stirring at roomtemperature overnight. The resin was removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (methylenechloride:methanol=20:1), and concentrated under reduced pressure. Theresidue (175 mg) was dissolved in ethyl acetate (5 ml). 1N—HCl-ethanolsolution (0.42 ml) was further added thereto, then crystals precipitatedwere filtered out and dried to obtain7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-1,2,3,4-tetrahydroquinolinehydrochloride (103 mg, yield: 37%) as white powder.

Melting point: 260.1-262.8° C.

Example 61 Preparation of4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxymethylamidedihydrochloride

Ethyl4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-quinolin-2-carboxylate(0.28 g) was added to a methanol solution of 40% methylamine (10 ml),followed by stirring at room temperature for two days. The reactionmixture was concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (ethylacetate:methanol=11:1), and concentrated under reduced pressure. Theresidue (166 mg) was dissolved in ethyl acetate. 1N—HCl-ethanol solution(0.7 ml) was further added thereto, then crystals precipitated werefiltered out and dried to obtain4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxymethylamidedihydrochloride (0.17 g, yield: 54%) as white powder.

Melting point: 224.0° C. (decomposed)

Example 62 Preparation of4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxylicacid hydrochloride

An aqueous solution of 4N lithium hydroxide (3 ml) was added to amethanol solution (7 ml) of ethyl4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-quinolin-2-carboxylate(1.5 g), followed by stirring at room temperature overnight. Then, water(10 ml) and aqueous solution (3 ml) of 4N lithium hydroxide were furtheradded, followed by stirring at 50° C. for 11 hours. The reaction mixturewas cooled in an ice-bath, and an aqueous solution (4 ml) of 6N—HCl wasadded thereto. Then, crystals precipitated were filtered out, washedwith water and dried to obtain4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxylicacid hydrochloride (1.43 g, yield: 98%) as white powder.

Melting point: 235.0° C.

Example 63 Preparation of4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxamide

Triethylamine (0.25 ml, 1.8 mmol) and isobutyl chloroformate (0.19 ml,1.4 mmol) were added to a solution (10 ml) of4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxylicacid (0.53 g, 1.2 mmol) in acetonitrile with cooling in an ice-bath,followed by stirring at 0° C. for 3 hours. 28% Aqueous ammonia (0.15 ml)was added thereto and the reaction mixture was stirred at roomtemperature for 5 minutes. Ethyl acetate was further added thereto, thenthe reaction mixture was washed with water and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (n-hexane:ethyl acetate=3:1), and concentrated underreduced pressure. The residue (0.2 g) was dissolved and recrystallizedfrom the mixed solvent of ethyl acetate and isopropyl ether to obtain4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-quuinolin-2-carboxamide(79 mg, yield: 16%) as white powder.

Melting point: 153.0-154.5° C.

Examples 64 to 196

Compounds of Example 64 to 196 shown in the following Tables 1 to 21 canbe prepared in the same manner as in Example 1, using correspondingstarting materials. In the following Tables, compounds with the physicalproperties, such as crystalline form, m.p. (melting point), salt, ¹H-NMRand MS (mass spectrum), were prepared actually.

TABLE 1

crystalline form (recrystallization Example No. R1 n solvent) m.p. (°C.) salt 64

3 white powder (methanol) 125-127 — 65

4 white powder (ethanol- ethyl acetate) 217-221 dihydrochloride 66

4 white powder (ethyl acetate) 123-130 (decomposed) —

TABLE 2

crystalline form (recrystallization Example No. R1 n solvent) m.p. (°C.) salt 67

3 white powder (ethanol) 253-255 (decomposed) hydrochloride 68

4 white powder (ethanol-ethyl acetate- acetonitrile) 151-153dihydrochloride 69

4 white powder (ethanol) 156-159 hydrochloride

TABLE 3

crystalline form (recrystallization Example No. R1 solvent) m.p. salt 70

colorless needle (ethanol) 106.0-108.0 — 71

white powder (ethanol) 192.0-194.0 hydrochloride 72

light yellow powder (ethanol) 240-242 hydrochloride 73

light yellow powder (ethanol) 199.0-201.0 hydrochloride 74

white powder (ethanol) 233.0-235.0 hydrochloride 75

yellow powder 199.0-204.5 dihydrochloride 76

white solid (ethyl acetate-hexane) 123.2-124.3 — 77

white solid (ethyl acetate) 231.3-232.9 hydrochloride 78

white solid (ethyl acetate) 229.6-231.3 hydrochloride 79

white powder (ethyl acetate) 237.0-238.5 hydrochloride 80

white solid (ethyl acetate) 214.5-216.8 hydrochloride

TABLE 4

crystalline form (recrystallization Example No. R1 solvent) m.p. salt 81

white solid (ethyl acetate) 207.9-208.7 hydrochloride 82

light yellow powder (ethyl acetate-isopropyl ether) 106.0-113.0 — 83

white powder (ethyl acetate-ether) 188-190 —

TABLE 5

Example No. R1 n 1H-NMR (solvent) salt 84

3 1H-NMR (CDCl3) δ ppm: 2.05-2.20 (2H, m), 2.65-2.77 (6H, m), 3.15-3.25(4H, m), 4.23 (2H, t, J = 6.3 Hz), 6.91 (1H, d, J = 7.1 Hz), 7.15-7.35(3H, m), 7.35-7.45 (3H, m), 7.55 (1H, d, J = 8.0 Hz), 7.70 (1H, d, J =8.9 Hz), 8.05-8.15 (1H, m), 8.83 (1H, dd, J = 1.7, 5.3 Hz). — 85

4 1H-NMR (DMSO-d6) d: 1.90-2.00 (4H, m), 3.25-3.40 (6H, m), 3.50-3.65(4H, m), 4.20-4.35 (2H, m), 6.95 (1H, d, J = 7.4 Hz), 7.30 (1H, dd, J =7.9, 7.9 Hz), 7.48 (1H, d, J = 5.5 Hz), 7.65-7.80 (3H, m), 7.80-7.95(2H, m), 8.32 (1H, d, J = 9.2 Hz), 9.05-9.20 (2H, m), 11.29 (1H, brs).dihydrochloride

TABLE 6

crystalline form (recrystallization Example No. R1 solvent) m.p. (° C.)salt 86

white powder (ethyl acetate) 239.6-241.5 hydrochloride 87

light brown powder (ethyl acetate) 228.3-229.5 hydrochloride 88

white powder (ethyl acetate) 212.3-214.4 hydrochloride 89

white powder (ethyl acetate) 232.9-235.1 hydrochloride 90

white powder (ethyl acetate) 165.8-167.9 hydrochloride 91

white powder (ethanol) 220-225 hydrochloride 92

white powder (ethanol) 221-224 hydrochloride 93

white powder (ethanol) 181-183 hydrochloride

TABLE 7

Example No. R1 n 1H-NMR (solvent) salt 94

3 1H-NMR (DMSO-d6) d: 2.01-2.12 (2H, m), 3.0-3.7 (16H, m), 6.98 (1H, d,J = 7.7 Hz), 7.29-7.39 (3H, m), 7.47-7.52 (2H, m), 7.70 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.6 Hz), 7.89 (1H, d, J = 7.7 Hz), 9.85 (1H, br-s)hydrochloride 95

2 1H-NMR (CDCl3) d: 3.0-4.1 (16H, m), 6.94 (1H, d, J = 7.4 Hz),7.20-7.47 (6H, m), 7.64 (1H, d, J = 8.1 Hz), 8.04 (1H, d, J = 7.4 Hz)oxalate

TABLE 8

crystalline form (recrystallization Example No. R1 solvent) m.p. (° C.)salt  96

white powder (ethyl acetate) 185.5-190.0 hydrochloride  97

white powder (ethyl acetate- ether) 134-136 —  98

white powder (ethyl acetate- ether) 103-105 —  99

white powder (ethyl acetate- ether) 126-128 — 100

white powder (ethyl acetate- ether) 97-99 — 101

brown powder (methanol) 240-242 hydrochloride 102

white powder (ethyl acetate- ether) 143-145 — 103

white powder (ethyl acetate- ether) 161-163 — 104

white powder (ethyl acetate- ether) 122-124 —

TABLE 9

crystalline form (recrystallization Example No. R1 solvent) m.p. (° C.)salt 105

white powder (ethyl acetate) 212.5-216.0 hydrochloride 106

white powder (ethyl acetate) 224.5-230.0 hydrochloride 107

white powder (ethyl acetate) 172.0-174.5 hydrochloride 108

white powder (ethyl acetate) 196.5-201.5 hydrochloride 109

white powder (ethyl acetate) 200.5-205.5 hydrochloride 110

white powder (ethyl acetate) 202.5-206.5 hydrochloride 111

white powder (ethyl acetate) 218.0-223.5 hydrochloride 112

white powder (ethyl acetate- isopropyl ether) 125.0-129.0 —

TABLE 10

MS Example No. R1  n  (M + 1) 113

3 454 114

3 501 115

3 448 116

3 440 117

3 434 118

3 438 119

3 502 120

3 457 121

3 420

TABLE 11

Example No. R1  n  MS (M + 1) 122

3 422 123

3 422 124

3 499 125

3 535 126

3 457 127

3 478 128

3 480 129

3

TABLE 12

Example MS No. R1  n  (M + 1) 130

3 499 131

3 434 132

3 133

3 434 134

3 528 135

3 465 136

3 450 137

3 462

TABLE 13

Example MS No. R1  n  (M + 1) 138

3 139

3 452 140

3 448 141

3 496 142

3 143

3 462 144

3 491 145

3

TABLE 14

Example MS No. R1  n  (M + 1) 146

3 498 147

3 148

3 464 149

3 501 150

3 480 151

3 462 152

3 467 153

3 467 154

3 452

TABLE 15

Example MS No. R1  n  (M + 1) 155

3 479 156

3 157

3 436 158

3 467 159

3 525 160

3 161

3 162

3 491

TABLE 16

Ex- am- ple MS No. R1  n  (M + 1) 163

3 491 164

3 494 165

3 166

3 167

3 168

3 479 169

3 519 170

3

TABLE 17

Example MS No. R1  n  (M + 1) 171

3 479 172

3 448 173

2 408 174

2 175

2 406 176

2 442 177

2 408 178

2 408 179

5 450 180

8 518

TABLE 18

Example No. R1  n  MS (M + 1) 181

4 471 182

4 183

4 469 184

4 452 185

4 448 186

4 436 187

4 436 188

4 434 189

4 450 190

3 438

TABLE 19

Example No. R1 MS (M + 1) 191

438 192

438 193

436

TABLE 20

Example No. R1 MS (M + 1) 194

436 195

436 196

434

TABLE 21

Example No. R1 MS (M + 1) 197

Pharmacological Test 1 1) Dopamine D₂ Receptor Binding Assay

The assay was performed according to the method by Kohler et al. (KohlerC, Hall H, Ogren S O and Gawell L, Specific in vitro and in vivo bindingof 3H-raclopride. A potent substituted benzamide drug with high affinityfor dopamine D-2 receptors in the rat brain. Biochem. Pharmacol., 1985;34: 2251-2259).

Wistar male rats were decapitated, the brain was retrieved immediatelyand corpus striatum was taken out. It was homogenized in 50 mMtris(hydroxymethyl)aminomethane (Tris)-hydrochloric acid buffer (pH 7.4)of a volume 50 times of the weight of the tissue using a homogenizerwith a high-speed rotating blade, and centrifuged at 4° C., 48,000×g for10 minutes. The obtained precipitate was suspended again in theabove-described buffer of a volume 50 times of the weight of the tissueand after incubated at 37° C. for 10 minutes, centrifuged in theabove-described condition. The obtained precipitate was suspended in 50mM (Tris)-hydrochloric acid buffer (containing 120 mM NaCl, 5 mM KCl, 2mM CaCl₂, 1 mM MgCl₂, pH 7.4) of a volume 25 times of the weight of thetissue and preserved by freezing at −85° C. till it was used for bindingassay as a membrane specimen.

The binding assay was performed using 40 μl of the membrane specimen, 20μl of [³H]-raclopride (final concentration 1 to 2 nM), 20 μl of a testdrug and 50 mM Tris-hydrochloric acid buffer (containing 120 mM NaCl, 5mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, pH 7.4) so that the total amount was 200μl (final dimethylsulfoxide concentration 1%). The reaction wasperformed at room temperature for 1 hour and terminated by conductingsuction filtration with a cell harvester on a glass fiber filter plate.The filter plate made of glass fiber was washed with 50 mMTris-hydrochloric acid buffer (pH 7.4), and after dried, a microplateliquid scintillation cocktail was added and the radioactivity wasmeasured with a microplate scintillation counter. Radioactivity in thepresence of 10 μM (+)-butaclamol hydrochloride was assumed asnonspecific binding.

IC₅₀ value was calculated from concentration-dependent reaction using anon-linear analysis program. Ki value was calculated from IC₅₀ valueusing Cheng-Prussoff formula. The results are shown in the followingTable 22.

TABLE 22 Test Compound Ki (nM) Compound of Example 1 0.2 Compound ofExample 3 0.5 Compound of Example 4 0.5 Compound of Example 5 0.6Compound of Example 6 0.8 Compound of Example 7 0.5 Compound of Example10 0.4 Compound of Example 11 0.1 Compound of Example 12 0.1 Compound ofExample 13 2.4 Compound of Example 14 3.2 Compound of Example 15 0.2Compound of Example 16 0.7 Compound of Example 17 2.2 Compound ofExample 18 2.6 Compound of Example 19 1.2 Compound of Example 20 1.5Compound of Example 22 4.0 Compound of Example 23 0.7 Compound ofExample 24 5.0 Compound of Example 26 3.5 Compound of Example 27 4.9Compound of Example 28 1.2 Compound of Example 30 0.7 Compound ofExample 31 1.4 Compound of Example 32 1.5 Compound of Example 33 1.1Compound of Example 34 1.2 Compound of Example 35 1.6 Compound ofExample 36 1.0 Compound of Example 37 1.9 Compound of Example 38 1.2Compound of Example 39 1.2 Compound of Example 40 4.8 Compound ofExample 41 1.9 Compound of Example 64 3.2 Compound of Example 68 1.0Compound of Example 69 0.8 Compound of Example 73 4.0 Compound ofExample 79 4.7 Compound of Example 80 1.5 Compound of Example 81 0.8Compound of Example 84 2.4 Compound of Example 85 2.0 Compound ofExample 90 0.4 Compound of Example 91 1.4 Compound of Example 92 1.7Compound of Example 116 4.5 Compound of Example 117 4.7 Compound ofExample 118 3.5 Compound of Example 122 3.3 Compound of Example 128 1.3Compound of Example 139 0.2 Compound of Example 155 2.3 Compound ofExample 163 2.8 Compound of Example 184 2.6 Compound of Example 185 2.7Compound of Example 186 2.3 Compound of Example 188 1.6 Compound ofExample 190 0.8

2) Serotonin 5-HT_(2A) Receptor Binding Assay

The assay was performed according to the method by Leysen J E et al.(Leysen J E, Niemegeers C J E, Van Nueten J M and Laduron P M. [3H]Ketanserin (R 41 468), a selective 3H-ligand for serotonin 2 receptorbinding sites. Mol. Pharmacol., 1982, 21: 301-314).

Wistar male rats were decapitated, the brain was retrieved immediatelyand frontal cortex was taken out. It was homogenized in 0.25 M sucroseof a volume 10 times of the weight of the tissue using a Teflon glasshomogenizer, and centrifuged at 4° C., 1,000×g for 10 minutes. Theobtained supernatant was transferred to another centrifuge tube andsuspended in 0.25 M sucrose of a volume 5 times of the weight of thetissue and the precipitate was centrifuged in the above-describedcondition. The obtained supernatant was combined with the supernatantobtained above and adjusted to a volume 40 times of the weight of thetissue with 50 mM Tris-hydrochloric acid buffer (pH 7.4), andcentrifuged at 4° C., 35,000×g for 10 minutes. The obtained precipitatewas suspended again in the above-described buffer of a volume 40 timesof the weight of the tissue and centrifuged in the above-describedcondition. The obtained precipitate was suspended in the above-describedbuffer of a volume 20 times of the weight of the tissue and preserved byfreezing at −85° C. till it was used for binding assay as a membranespecimen.

The binding assay was performed using 40 μl of the membrane specimen, 20μl of [³H]-Ketanserin (final concentration 1 to 3 nM), 20 μl of a testdrug and 50 mM Tris-hydrochloric acid buffer (pH 7.4) so that the totalamount was 200 μl (final dimethylsulfoxide concentration 1%). Thereaction was performed at 37° C. for 20 minutes and terminated byconducting suction filtration with a cell harvester on a glass fiberfilter plate.

The filter plate made of glass fiber was washed with 50 mMTris-hydrochloric acid buffer (pH 7.4), and after dried, a microplateliquid scintillation cocktail was added and the radioactivity wasmeasured with a microplate scintillation counter. Radioactivity in thepresence of 10 μM spiperone was assumed as nonspecific binding.

IC₅₀ value was calculated from concentration-dependent reaction using anon-linear analysis program. Ki value was calculated from IC₅₀ valueusing Cheng-Prussoff formula. The results are shown in the followingTable 23.

TABLE 23 Test Compound Ki (nM) Compound of Example 1 2.3 Compound ofExample 2 1.5 Compound of Example 3 2.3 Compound of Example 4 4.9Compound of Example 5 6.4 Compound of Example 7 4.0 Compound of Example8 0.6 Compound of Example 9 2.6 Compound of Example 10 3.0 Compound ofExample 11 5.7 Compound of Example 12 2.1 Compound of Example 15 3.3Compound of Example 16 7.0 Compound of Example 17 2.8 Compound ofExample 18 8.0 Compound of Example 19 1.2 Compound of Example 20 3.3Compound of Example 21 1.0 Compound of Example 22 2.9 Compound ofExample 23 1.7 Compound of Example 24 2.3 Compound of Example 25 4.6Compound of Example 26 4.4 Compound of Example 27 4.1 Compound ofExample 28 2.8 Compound of Example 30 2.0 Compound of Example 31 4.5Compound of Example 32 8.6 Compound of Example 33 6.6 Compound ofExample 34 1.5 Compound of Example 35 2.1 Compound of Example 36 2.1Compound of Example 37 3.1 Compound of Example 38 7.3 Compound ofExample 39 2.1 Compound of Example 40 5.1 Compound of Example 41 3.2Compound of Example 64 8.2 Compound of Example 68 7.0 Compound ofExample 69 6.1 Compound of Example 73 1.3 Compound of Example 79 5.5Compound of Example 80 2.5 Compound of Example 81 2.6 Compound ofExample 84 3.3 Compound of Example 89 3.1 Compound of Example 90 5.3Compound of Example 91 6.5 Compound of Example 92 5.7 Compound ofExample 116 4.2 Compound of Example 117 1.3 Compound of Example 118 3.4Compound of Example 122 2.9 Compound of Example 128 6.3 Compound ofExample 139 4.0 Compound of Example 155 3.0 Compound of Example 163 7.4Compound of Example 184 4.3 Compound of Example 185 5.0 Compound ofExample 186 8.8 Compound of Example 188 6.3 Compound of Example 190 2.9

3) Adrenalin α1 Receptor Binding Assay

The assay was performed according to the method by Groβ G et al. (GroβG, Hanft G and Kolassa N. Urapidil and some analogues with hypotensiveproperties show high affinities for 5-hydroxytryptamine (5-HT) bindingsites of the 5-HT1A subtype and for α1-adrenoceptor binding sites.Naunyn-Schmiedeberg's Arch Pharmacol., 1987, 336: 597-601).

Wistar male rats were decapitated, the brain was retrieved immediatelyand cerebral cortex was taken out. It was homogenized in 50 mMTris-hydrochloric acid buffer (100 mM NaCl, containing 2 mM dihydrogendisodium ethylene diamine tetraacetate, pH 7.4) of a volume 20 times ofthe weight of the tissue using a homogenizer with a high-speed rotatingblade, and centrifuged at 4° C., 80,000×g for 20 minutes. The obtainedprecipitate was suspended in the above-described buffer of a volume 20times of the weight of the tissue and after incubated at 37° C. for 10minutes, centrifuged in the above-described condition. The obtainedprecipitate was suspended again in the above-described buffer of avolume 20 times of the weight of the tissue and centrifuged in theabove-described condition. The obtained precipitate was suspended in 50mM (Tris)-hydrochloric acid buffer (containing 1 mM dihydrogen disodiumethylene diamine tetraacetate, pH 7.4) of a volume 20 times of theweight of the tissue and preserved by freezing at −85° C. till it wasused for binding assay as a membrane specimen.

The binding assay was performed using 40 μl of the membrane specimen, 20μl of [³H]-prazosin (final concentration 0.2 to 0.5 nM), 20 μl of a testdrug and 50 mM Tris-hydrochloric acid buffer (containing 1 mM EDTA, pH7.4) so that the total amount was 200 μl (final dimethylsulfoxideconcentration 1%). The reaction was performed at 30° C. for 45 minutesand terminated by conducting suction filtration with a cell harvester ona glass fiber filter plate.

The filter plate made of glass fiber was washed with 50 mMTris-hydrochloric acid buffer (pH 7.4), and after dried, a microplateliquid scintillation cocktail was added and the radioactivity wasmeasured with a microplate scintillation counter. Radioactivity in thepresence of 10 μM phentolamine hydrochloride was assumed as nonspecificbinding.

IC₅₀ value was calculated from concentration-dependent reaction using anon-linear analysis program. Ki value was calculated from IC₅₀ valueusing Cheng-Prussoff formula.

Pharmacological Test 2

Partial Agonistic Activity on Dopamine D₂ Receptor Using D₂ ReceptorExpression Cells

Partial agonistic activity on dopamine D₂ receptor was evaluated byquantitatively determining cyclic AMP production inhibitory effect of atest compound in dopamine D₂ receptor expression cells in whichadenosine 3′,5′-cyclic monophosphate (cyclic AMP) production was inducedby forskolin stimulation.

Human recombinant dopamine D₂ receptor expressing Chinese hamsterovary/DHFR(−) cells were cultured in a culture medium (Iscove's ModifiedDulbecco's Medium (IMDM culture medium), 10% fetal bovine serum, 50I.U./ml penicillin, 50 μg/ml streptomycin, 200 μg/ml geneticin, 0.1 mMsodium hypoxanthine, 16 M thymidine) at 37° C. and 5% carbon dioxidecondition. Cells were seeded at 10⁴ cells/well on a 96-well microtiterplate coated with poly-L-lysine and grown under the same condition for 2days. Each well was washed with 100 μl of a culture medium (IMDM culturemedium, 0.1 mM sodium hypoxanthine, 16 μM thymidine). The culture mediumwas replaced with 50 μl of culture medium (IMDM culture medium, 0.1%sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 μM thymidine) havingdissolved therein 3 μM of a test compound. After allowed to incubate at37° C., 5% carbon dioxide condition for 20 minutes, the culture mediumwas replaced with 100 μl of forskolin stimulative culture medium (IMDMculture medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 μMthymidine, 10 μM forskolin, 500 μM 3-isobutyl-1-methylxanthine) having 3μM of the test compound dissolved therein and allowed to incubate at 37°C., 5% carbon dioxide condition for 10 minutes. After the culture mediumwas removed, 200 μl of Lysis 1B aqueous solution (Amersham Bioscience,reagent attached to cyclic AMP biotrack enzyme immunoassay system) wasdispensed and shaken for 10 minutes. The aqueous solution of each wellwas used as a sample for measurement. Samples for measurement quadruplydiluted were subjected to measurement of the quantity of cyclic AMPusing the above-described enzyme immunoassay system. Inhibition ratio ofthe respective test compound was calculated assuming that the quantityof cyclic AMP of the well to which no test compound was added was 100%.In this empiric test system, dopamine which was used as a control drugsuppressed the quantity of cyclic AMP to about 10% as the maximumactivity.

It was confirmed that test compounds had partial agonistic activity fordopamine D₂ receptor in the above-described test.

Since the test compounds has partial agonistic activity for dopamine D₂receptor, they can stabilize dopamine neurotransmission to a normalcondition in a schizophrenia patient and as a result, exhibit, forexample, positive and negative condition improving effect, cognitiveimpairment improving effect and the other symptom improving effectswithout causing side effects.

Pharmacological Test 3

Inhibitory Effect on Apomorphine-Induced Stereotyped Behavior in Rats

Wistar rats (male, six-seven weeks old, Japan SLC, Inc.) were used astest animals. A test compound was suspended in 5% gumarabic/(physiological saline or water) using an agate mortar and wasdiluted with the same solvent if necessary.

Test animals were fasted overnight from the day before. Apomorphine (0.7mg/kg) was subcutaneously administered (1 ml/kg) 1 hour after each testcompound was orally administered (5 ml/kg). Stereotyped behavior wasobserved for 1 minute respectively 20, 30 and 40 minutes afterapomorphine injection.

The stereotyped behavior of each animal was quantified according to thefollowing condition and score made at three points were summed up andthe anti-apomorphine effect was evaluated. Six test animals were usedfor each group.

0: The appearance of the animals is the same as saline treated rats;

1: Discontinuous sniffing, constant exploratory activity;

2: Continuous sniffing, periodic exploratory activity;

3: Continuous sniffing, discontinuous biting, gnawing or licking. Verybrief periods of locomotor activity;

4: Continuous biting, gnawing or licking; no exploratory activity.

Non-clinical statistical analysis system was used for all statisticalprocessing. When the significance probability value was lower than 0.05,it was judged that a significant difference existed. The difference ofthe score between the solvent administration group and each testcompound administration group was analyzed using Wilcoxon rank-sum testor Steel test. In addition, linear regression analysis was used forcalculating 50% effective dose (95% confidence interval).

Since the test compounds showed inhibitory effect forapomorphine-induced stereotyped behavior, it was confirmed that the testcompounds have D₂ receptor antagonistic effect.

Pharmacological Test 4

Inhibitory Effect on (±)D-2,5-Dimethoxy-4-Iodoamphetamine (DOI) InducedHead Twitch in Rats

Wistar rats (male, six-seven weeks old, Japan SLC, Inc.) were used astest animals. A test compound was suspended in 5% gumarabic/(physiological saline or water) using an agate mortar and wasdiluted with the same solvent if necessary.

Test animals were fasted overnight from the day before. DOI (5.0 mg/kg)was subcutaneously administered (1 ml/kg) 1 hour after each testcompound was orally administered (5 ml/kg). The number of head twitcheswas counted for 10 minutes immediately after DOI injection. Six testanimals were used for each group.

Non-clinical statistical analysis was used for all statisticalprocessing. When the significance probability value was lower than 0.05,it was judged that a significant difference existed. The difference ofthe number of head twitches between the solvent administration group andeach test compound administration group was analyzed using t-test orDunnett's test. In addition, linear regression analysis was used forcalculating 50% effective dose (95% confidence interval).

Since the test compounds showed inhibitory effect for DOI-induced headtwitch, it was confirmed that the test compounds have serotonin 5HT_(2A)receptor antagonistic effect.

Pharmacological Test 5

Catalepsy Inducing Effect in Rats

Wistar rats (male, six-seven weeks old, Japan SLC, Inc.) were used astest animals. A test compound was suspended in 5% gumarabic/(physiological saline or water) using an agate mortar and wasdiluted with the same solvent if necessary.

Test animals were fasted overnight from the day before observation oncatalepsy and ptosis was performed 1, 2, 4, 6 and 8 hours after eachtest compound was orally administered (5 ml/kg). Six test animals wereused for each group.

One forepaw of a rat was placed on an edge of a steel small box (width:6.5 cm, depth: 4.0 cm, height: 7.2 cm) (an unnatural pose) and when therat maintained the pose for more than 30 seconds, it was judged that thecase was catalepsy positive. This observation was performed three timesat each point, and if there was at least one positive case, it wasjudged that catalepsy occurred in the individual.

As a result, catalepsy induction effect of a test compound wasdissociated from inhibitory effect on apomorphine-induced stereotypedbehavior, therefore it was suggested that apprehension forextrapyramidal side effect in clinic would be low.

Pharmacological Test 6

Measurement of Serotonin (5-HT) Uptake Inhibitory Activity of a TestCompound by Rat Brain Synaptosome

Wistar male rats were decapitated, the brain was retrieved and frontalcortex was dissected out, and it was homogenized in 0.32 M sucrosesolution of a weight 20 times of the weight of the tissue using a Pottertype homogenizer. The homogenate was centrifuged at 4° C., 1,000×g for10 minutes, the obtained supernatant was further centrifuged at 4° C.,20,000×g for 20 minutes, and the pellet was suspended in an incubationbuffer (20 mM Hepes buffer (pH 7.4) containing 10 mM glucose, 145 mMsodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride,1.5 mM calcium chloride), which was used as crude synaptosome fraction.

5-HT uptake reaction was performed in a volume of 200 μl using a 96-wellround bottom plate and pargyline (final concentration 10 μM) and sodiumascorbate (final concentration 0.2 mg/ml) were contained in theincubation buffer upon reaction and used.

Incubation buffer (total counting), non-labeled 5-HT (finalconcentration 10 μM, non-specific counting) and the diluted testcompound (final concentration 300 nM) were added to each well. One-tenthquantity of the final volume of the synaptosome fraction was added andafter preincubated at 37° C. for 10 minutes, tritium labeled 5-HTsolution (final concentration 8 nM) was added and uptake reaction wasstarted at 37° C. The uptake time was 10 minutes and the reaction wasterminated by vacuum filtration through a 96-well fiber glass filterpaper plate, and after the filter paper was washed with cold normalsaline, it was dried enough and Microscint0 (Perkin-Elmer) was added tothe filter and remaining radioactivity on the filter was measured.

Serotonin uptake inhibitory activity (%) was calculated from theradioactivity of total counting as 100%, of non-specific counting as 0%,and of counting obtained with test compound.

% of inhibition of 5-HT (%)=100−[(Count obtained with testcompound-Nonspecific count(0% Uptake))/(Total count(100%Uptake)−Nonspecific count (0% Uptake))]×100

The results are shown in the next Table 24.

TABLE 24 Serotonin uptake inhibitory Test compound ratio (%) (300 nM)Compound of Example 1 92.4 Compound of Example 2 78.8 Compound ofExample 3 84.8 Compound of Example 4 91.0 Compound of Example 5 89.1Compound of Example 6 91.3 Compound of Example 7 91.0 Compound ofExample 8 95.0 Compound of Example 9 97.3 Compound of Example 10 92.6Compound of Example 11 92.5 Compound of Example 13 77.0 Compound ofExample 14 85.2 Compound of Example 15 87.2 Compound of Example 16 86.7Compound of Example 17 86.3 Compound of Example 18 91.1 Compound ofExample 19 86.3 Compound of Example 20 92.8 Compound of Example 21 81.4Compound of Example 22 90.8 Compound of Example 23 95.5 Compound ofExample 24 97.5 Compound of Example 25 91.9 Compound of Example 26 92.0Compound of Example 27 94.0 Compound of Example 28 95.3 Compound ofExample 30 95.8 Compound of Example 31 96.3 Compound of Example 32 96.9Compound of EXample 33 94.3 Compound of Example 34 94.2 Compound ofExample 35 93.4 Compound of Example 36 97.4 Compound of Example 37 97.7Compound of Example 38 96.7 Compound of Example 39 99.2 Compound ofExample 40 91.6 Compound of Example 41 95.1 Compound of Example 64 73.0Compound of Example 65 72.9 Compound of Example 66 74.1 Compound ofExample 67 93.9 Compound of Example 68 95.7 Compound of Example 69 96.3

Preparation Examples

100 g of a compound of the present invention, 40 g of Avicel (tradename, product of Asahi Chemical Industry Co., Ltd.), 30 g of corn starchand 2 g of magnesium stearate was mixed and polished and tableted with apestle for glycocalyx R10 mm.

The obtained tablet was coated with a film using a film coating agentmade up of 10 g of TC-5 (trade name, product of Shin-Etsu Chemical Co.,Ltd., hydroxypropyl methylcellulose), 3 g of polyethylene glycol 6000,40 g of castor oil and an appropriate amount of ethanol to produce afilm coated tablet of the above composition.

1-16. (canceled)
 17. A method for treating obesity comprisingadministering a heterocyclic compound represented by the formula (1) ora salt thereof to a human or animal:

wherein ring Q represented by

represents

wherein

represents —NH—CH₂—, —CH₂—NH— or —CH═N—; and the carbon-carbon bond

between the 3-position and 4-position of the heterocyclic skeletoncontaining Z and Y represents a single bond or a double bond; the ring Qmay have at least one substituent selected from the group consisting ofa lower alkyl group, a lower alkenyl group, a lower alkynyl group, ahydroxy group, a lower alkoxy group, a halogenated lower alkyl group, anaryl group, an aryl lower alkyl group, an aryl lower alkoxy group, anarylcarbonyl group, a lower alkenyloxy group, a lower alkanoyl group, alower alkanoyloxy group, a cycloalkyl group, a cycloalkyl lower alkylgroup, a halogen atom, a carbamoyl group which may have a lower alkylgroup, a carboxy group, a lower alkoxycarbonyl group, an amino groupwhich may have a lower alkanoyl group, a nitro group, a hydroxy loweralkyl group, an amino lower alkyl group which may have a lower alkylgroup, a thienyl group, a saturated 3 to 8-membered heteromonocyclicgroup containing 1 to 2 nitrogen atoms-substituted lower alkyl group andan oxo group; R₂ represents a hydrogen atom or a lower alkyl group; andA represents —O-A₁- (wherein A₁ represents an alkylene group which maybe substituted with a hydroxy group (wherein the one oxygen atom mayreplace a carbon of the alkylene chain) or a lower alkenylene group) ora lower alkylene group; provided that when A represents a lower alkylenegroup, the ring Q represents a bicyclic group selected from the groupconsisting of:

wherein the carbon-carbon-bond

represents a single bond or a double bond.
 18. The method according toclaim 17, wherein the heterocyclic compound of the formula (1) isselected from the group consisting of: (1)7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one,(2)7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-quinolin-2-one,(3)7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one,(4)7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one,(5)7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1-methyl-3,4-dihydro-1H-1-quinolin-2-oneand (6)6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one;or a salt thereof.
 19. The method according to claim 17, wherein theheterocyclic compound of the formula (1) is selected from the group of:(1)7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-one(2)7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one,(3)7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one,(4)7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yi)butoxy]-3,4-dihydro-2H-isoquinoline-1-one,(5)7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2H-isoquinolin-1-oneand (6)7-[3-(4-benzo(b)thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-2H-isoquinolin-1-one;or a salt thereof.
 20. The method according to claim 18, wherein theheterocyclic compound of formula (1) is7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.